JP6731036B2 - Method for producing polyalkylene glycol derivative having amino group at terminal, polymerization initiator used therefor, and alcohol compound as raw material thereof - Google Patents

Description

The present invention relates to a method for producing a polyalkylene glycol derivative having an amino group at a terminal, a polymerization initiator used for the method, and an alcohol compound as a raw material thereof.

In recent years, in the field of drug delivery systems, a method of encapsulating a drug in a polymer micelle using a block copolymer formed of a hydrophilic segment and a hydrophobic segment has been proposed (for example, Patent Documents 1 to 3). See). By using this method, the polymer micelle functions as a carrier for the drug, and various effects including sustained release of the drug in the body and intensive administration to the lesion site can be obtained.

As the hydrophilic segment, many examples using a polyalkylene glycol skeleton have been proposed (see, for example, Patent Documents 1 to 3). A compound having a polyalkylene glycol skeleton has low toxicity in vivo and can delay excretion in the kidney. As a result, the residence time in blood can be extended as compared with a compound having no polyalkylene glycol skeleton. Therefore, when a drug is formed into a micelle with a polyalkylene glycol derivative and used, the dose and the number of doses can be reduced.

Among the polyalkylene glycol derivatives, the compound having an amino group at the terminal is derived into a block copolymer composed of a polyalkylene glycol skeleton and an amino acid skeleton by a ring-opening polymerization reaction with α-amino acid-N-carboxyanhydride. It is possible. And many examples of encapsulating a drug in a polymer micelle using the obtained block copolymer have been proposed (see, for example, Patent Documents 1 to 3).

Such a method for synthesizing a polyalkylene glycol derivative having an amino group at the terminal is also known (for example, see Patent Documents 4 and 5). In these methods, after the alkylene oxide is polymerized by using a metal salt of a monohydric alcohol as a polymerization initiator, the polymerization terminal is converted into a hydroxyl group and then a 2-cyanoethoxy group, and the cyano group is hydrogen-reduced to give a final product. To an amino group-containing substituent (3-amino-1-propoxy group).

As another method for synthesizing a polyalkylene glycol derivative having an amino group, for example, a method in which a polymerization initiator in which an amino group is silyl protected is used to polymerize with ethylene oxide, and then the compound is deprotected to be an amino group (non-patent document) However, this method has a problem that the terminal is limited to a 2-amino-1-ethoxy group. Also,
Reactivity is low, and it has been a problem that it takes a long time of 96 hours to increase the molecular weight to 6000 (see Non-Patent Document 1).

Japanese Patent No. 2690276 Japanese Patent No. 2777530 JP-A-11-335267 Japanese Patent No. 3050228 Japanese Patent No. 3562000 Japanese Patent No. 4581248

Bioconj. Chem. 1992, 3, 275-276.

As disclosed in Patent Document 4, it is difficult to completely dissolve a metal salt of a monohydric alcohol used as a polymerization initiator in a polymerization solvent (for example, an organic solvent such as tetrahydrofuran (hereinafter abbreviated as THF)). In many cases, in order to dissolve the metal salt in the polymerization solvent, it is necessary to leave an excessive amount of alcohol as an initiator raw material during the synthesis of the metal salt (for example, in Patent Document 4, a polymerization initiator is used). 13 mol of methanol for 2 mol of certain sodium methoxide). However, when these alcohols are present in the reaction system, a decrease in the polymerization rate is inevitable, and strict reaction conditions such as high temperature and high pressure are required to increase the polymerization rate. Further, if the polymerization initiator is not dissolved in the polymerization solvent, the inside of the system will not be uniform, so that the polymerization will proceed only from the dissolved polymerization initiator and the polyalkylene glycol derivative obtained will have a wide dispersity.

Further, the monohydric alcohol often contains a trace amount of water. When a polymerization initiator is prepared in a water-containing state and polymerized with an alkylene oxide, a polymer compound having hydroxyl groups at both terminals (hereinafter,
A diol polymer is abbreviated). If the boiling point of the monohydric alcohol is sufficiently higher than that of water, the water content can be reduced by dehydration under reduced pressure. It cannot be dehydrated below to remove water. Therefore, when a metal salt is prepared using methanol and alkylene oxide is polymerized, formation of a diol polymer is unavoidable. A diol polymer is extremely difficult to separate and purify because its physical properties such as structure and molecular weight are similar to those of the target product. When the above reaction is allowed to proceed with the diol polymer contained as an impurity, a polymer containing amino groups at both ends is produced unless proper reaction conditions are selected. If such a polymer containing impurities is used as it is, the intended performance may not be obtained in the design of the polymer micelle agent, and therefore, the water content should be kept as low as possible during the polymerization reaction.

In the synthesis methods described in Patent Documents 4 and 5, a cyano group is converted to an aminomethyl group by hydrogen reduction using a Raney nickel catalyst. In this method, there is a possibility that a trace amount of metal may be mixed in the final product depending on the use of the polyalkylene glycol derivative. Furthermore, this reaction generally requires high temperature, which leads to the β-value of acrylonitrile.
Desorption progresses and the target product cannot be obtained in good yield, secondary amine and tertiary amine produced by amine addition reaction to imine, which is an intermediate of nitrile reduction, and by-product of polyacrylonitrile. There was also a problem that there was a risk of.

As a method for synthesizing a polyalkylene glycol derivative having an amino group at the terminal without using a heavy metal, a method in which an alkoxide having a protected amino group is used as a polymerization initiator to polymerize with an alkylene oxide can be considered. For example, when a silyl group is used as a protecting group for an amino group, since the silicon-nitrogen bond is weaker than the silicon-oxygen bond, it is very difficult to selectively synthesize an alcohol in which only an amino group is silylated. No examples have been reported.

It is an object of the present invention to solve the above-mentioned problems in the prior art and to provide a method for producing a polyalkylene glycol derivative having a terminal amino group with a narrow dispersion and high purity, and a polymerization initiator used in the method. And

The present inventors have conducted extensive studies in order to achieve the above object, and as a result of using a compound having a sufficient solubility in a polymerization solvent in which an amino group is protected by a protecting group, as a polymerization initiator, it is mild. Polymerization of alkylene oxide under conditions, suppression of diol polymer formation, removal of diol polymer when it is possible, and prevention of heavy metal contamination and by-product formation are realized. The present inventors have completed the present invention by finding that they can be derived into highly pure and narrowly dispersed polyalkylene glycol having an amino group at the terminal.

（一般式（Ｉ）中、Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一
方が水素原子を示し、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互
いに結合してアミノ基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数
１〜６の直鎖状、又は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ
_Ａ ^３は単結合、或いはヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素
数３〜２０の分岐状もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の
炭素数の総数は４以上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３
の炭素原子及びヘテロ原子の総数が４以上であり、Ｍはアルカリ金属を表す） That is, the present invention uses a compound represented by the following general formula (I) as a polymerization initiator,
The present invention relates to a method for producing a polyalkylene glycol derivative having an amino group at a terminal, which comprises at least a step of reacting the polymerization initiator with an alkylene oxide.

(In the general formula (I), R _A ^1a and R _A ^1b each independently represent a protecting group for an amino group, one of them represents a hydrogen atom, and the other represents a protecting group of an amino group, or R _A ^1a And R _A ^1b represent a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbons, or a branched or cyclic having 3 to 6 carbons. R is a divalent hydrocarbon group of
_A ³ is a single bond, or a linear or branched C 1-20 hydrocarbon group which may contain a hetero atom, or a branched or cyclic C 3-20 divalent hydrocarbon group, wherein R _A ² and the total number of carbon atoms of _R ^{a 3} is four or more, _{or, if R} ^{a 3} is a hetero atom _R ^{a 2} and _R ^{a 3}
The total number of carbon atoms and hetero atoms is 4 or more, and M represents an alkali metal)

（一般式（Ｉ）〜（ＩＩＩ）中、
Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一方が水素原子を示し
、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに結合してアミノ
基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数１〜６の直鎖状、又
は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ_Ａ ^３は単結合、或い
はヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素数３〜２０の分岐状
もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の炭素数の総数は４以
上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３の炭素原子及びヘテ
ロ原子の総数が４以上であり、Ｒ_Ａ ^４は水素原子、或いは置換されていてもよい直鎖状、
分岐状又は環状の炭素数１〜１２の炭化水素基であり、かつ該炭化水素基はヘテロ原子を
含んでいてもよく、Ｒ_Ａ ^５は炭素数２〜８のアルキレン基であり、Ｍはアルカリ金属を表
し、ｎは１〜４５０の整数である）
工程ａ）前記一般式（Ｉ）で表される重合開始剤とアルキレンオキシドとを重合溶媒中で
反応させることにより、下記一般式（Ｉ−１）で表される化合物を得る工程

（一般式（Ｉ−１）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＲ_Ａ ^５は前記一般式
（ＩＩ）及び（ＩＩＩ）について定義したとおりであって、前記一般式（ＩＩ）及び（Ｉ
ＩＩ）のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＲ_Ａ ^５と同一であり、Ｍはアルカリ
金属を表し、前記一般式（Ｉ）のＭと同一であり、ｒは１〜４４５の整数を表す）；
工程ｂ）前記一般式（Ｉ−１）で表される化合物と下記一般式（Ｉ−２）で表される化合
物とを反応させることにより、前記一般式（ＩＩ）で表される化合物を得る工程

（一般式（Ｉ−２）中、Ｒ_Ａ ^４及びＲ_Ａ ^５は前記一般式（ＩＩ）及び（ＩＩＩ）について
定義したとおりであって、前記一般式（ＩＩ）及び（ＩＩＩ）のＲ_Ａ ^４及びＲ_Ａ ^５と同一
であり、ｋは０〜５の整数を表し、Ｌは脱離基を表す）；及び
工程ｃ）前記一般式（ＩＩ）で表される化合物を脱保護し、前記一般式（ＩＩＩ）で表さ
れる化合物を得る工程。 According to another aspect, the present invention relates to a method for producing a polyalkylene glycol derivative having a terminal amino group, which comprises steps a) to c).

(In the general formulas (I) to (III),
R _A ^1a and R _A ^1b each independently represent a protecting group for an amino group, one of them represents a hydrogen atom, and the other represents a protecting group of an amino group, or R _A ^1a and R _A ^1b are bonded to each other. Represents a cyclic protecting group that forms a ring together with the nitrogen atom of the amino group, and R _A ² is a straight-chain C 1-6, or branched or cyclic C 3-6 divalent hydrocarbon group. R _A ³ is a single bond, or a linear or branched C 1-20 hydrocarbon group which may contain a hetero atom, or a branched or cyclic C 3-20 divalent hydrocarbon group, And the total number of carbon atoms of R _A ² and R _A ³ is 4 or more, or when R _A ³ contains a hetero atom, the total number of carbon atoms and hetero atoms of R _A ² and R _A ³ is 4 or more. R _A ⁴ is a hydrogen atom or an optionally substituted straight chain,
It is a branched or cyclic hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group may contain a hetero atom, R _A ⁵ is an alkylene group having 2 to 8 carbon atoms, and M is an alkali. Represents a metal, and n is an integer of 1 to 450)
Step a) A step of obtaining a compound represented by the following general formula (I-1) by reacting the polymerization initiator represented by the general formula (I) with an alkylene oxide in a polymerization solvent.

(In the general formula (I-1), R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ⁵ are as defined for the general formulas (II) and (III), and Formulas (II) and (I
II) is the same as R _A ^1a , R _A ^1b , R _A ² , R _A ³ , and R _A ⁵ , M is an alkali metal, and is the same as M in the general formula (I), and r is Represents an integer of 1 to 445);
Step b) A compound represented by the general formula (II) is obtained by reacting the compound represented by the general formula (I-1) with a compound represented by the following general formula (I-2). Process

(In the general formula (I-2), R _A ⁴ and R _A ⁵ are as defined for the general formulas (II) and (III), and R _A ^{4 in the} general formulas (II) and (III) are the same. And R _A ⁵ and k represents an integer of 0 to 5 and L represents a leaving group); and step c) deprotecting the compound represented by the general formula (II), A step of obtaining a compound represented by the formula (III).

（一般式（ｉ）中、Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一
方が水素原子を示し、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互
いに結合してアミノ基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数
１〜６の直鎖状、又は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ
_Ａ ^３は単結合、或いはヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素
数３〜２０の分岐状もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の
炭素数の総数は４以上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３
の炭素原子及びヘテロ原子の総数が４以上である） Another aspect of the present invention relates to a protected amino group-containing alcohol compound represented by the following general formula (i).

(In the general formula (i), R _A ^1a and R _A ^1b each independently represent a protecting group for an amino group, one of them represents a hydrogen atom, and the other represents a protecting group for an amino group, or R _A ^1a And R _A ^1b represent a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbons, or a branched or cyclic having 3 to 6 carbons. R is a divalent hydrocarbon group of
_A ³ is a single bond, or a linear or branched C 1-20 hydrocarbon group which may contain a hetero atom, or a branched or cyclic C 3-20 divalent hydrocarbon group, wherein R _A ² and the total number of carbon atoms of _R ^{a 3} is four or more, _{or, if R} ^{a 3} is a hetero atom _R ^{a 2} and _R ^{a 3}
The total number of carbon atoms and heteroatoms is 4 or more)

（一般式（Ｉ）中、Ｒ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互いに独立にアミノ基の保護基を示すか、一
方が水素原子を示し、他方がアミノ基の保護基を示すか、又はＲ_Ａ ^１ａ及びＲ_Ａ ^１ｂは互
いに結合してアミノ基の窒素原子と共に環を形成する環状保護基を示し、Ｒ_Ａ ^２は炭素数
１〜６の直鎖状、又は炭素数３〜６の分岐状もしくは環状の２価の炭化水素基であり、Ｒ
_Ａ ^３は単結合、或いはヘテロ原子を含んでいてもよい炭素数１〜２０の直鎖状、又は炭素
数３〜２０の分岐状もしくは環状の２価の炭化水素基であり、ここでＲ_Ａ ^２及びＲ_Ａ ^３の
炭素数の総数は４以上であり、又は、Ｒ_Ａ ^３がヘテロ原子を含む場合はＲ_Ａ ^２及びＲ_Ａ ^３
の炭素原子及びヘテロ原子の総数が４以上であり、Ｍはアルカリ金属を表す） According to still another aspect, the present invention relates to a metal salt of a protected amino group-containing alcohol compound represented by the following general formula (I).

(In the general formula (I), R _A ^1a and R _A ^1b each independently represent a protecting group for an amino group, one of them represents a hydrogen atom, and the other represents a protecting group of an amino group, or R _A ^1a And R _A ^1b represent a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group, and R _A ² is a straight chain having 1 to 6 carbons, or a branched or cyclic having 3 to 6 carbons. R is a divalent hydrocarbon group of
_A ³ is a single bond, or a linear or branched C 1-20 hydrocarbon group which may contain a hetero atom, or a branched or cyclic C 3-20 divalent hydrocarbon group, wherein R _A ² and the total number of carbon atoms of _R ^{a 3} is four or more, _{or, if R} ^{a 3} is a hetero atom _R ^{a 2} and _R ^{a 3}
The total number of carbon atoms and hetero atoms is 4 or more, and M represents an alkali metal)

By using the method for producing a polyalkylene glycol derivative having an amino group at the terminal according to the present invention, it becomes possible to carry out the polymerization without the substantial presence of a polymerization initiator raw material alcohol, which is a cause of decreasing the polymerization rate. The alkylene oxide can be polymerized under mild conditions. Further, it is possible to suppress the generation of impurities such as diol polymer due to a trace amount of water, and even if water is mixed and polymer impurities are generated, it can be removed by separation and purification, so that polydispersion of narrow dispersion and high purity is achieved. Alkylene glycol derivatives can be produced. If this method also includes a purification step, freeze-drying is not required when purifying and removing the polyalkylene glycol derivative, and thus the polyalkylene glycol derivative can be produced on an industrial scale, and the equipment and process It has the further advantage that simplification can be realized. In addition, by using a polymerization initiator with protected amino groups, it is possible to avoid the use of a reduction method using heavy metals and to prevent the inclusion of by-products that accompany it. It is possible to reduce the risk of product contamination. Furthermore, the polyalkylene glycol derivative produced by the production method according to the present invention is narrowly dispersible because the polymerization initiator is uniformly dissolved in the system, and is a hydrophilic segment useful in the field of drug delivery systems. It can be used very advantageously in the derivation of block copolymers formed from hydrophobic segments. Furthermore, the alcohol compound protected with an amino group and the alkali metal salt thereof according to the present invention can be used as a more useful polymerization initiator and a precursor thereof, which are conventional alternatives in the method for producing a polyalkylene glycol derivative. Very useful.

[Embodiment 1]
The present invention provides a polyalkylene glycol derivative having an amino group at a terminal, which comprises using a compound represented by the following general formula (I) as a polymerization initiator and at least including a step of reacting the polymerization initiator with an alkylene oxide. It is a manufacturing method. According to one embodiment, the invention provides
It is characterized in that the following steps a) to c) are sequentially performed. (Hereinafter, this embodiment may be referred to as "embodiment 1".)
Step a) a step of reacting a polymerization initiator represented by the general formula (I) with an alkylene oxide in a polymerization solvent to obtain a compound represented by the following general formula (I-1),
Step b) a step of reacting a compound represented by the general formula (I-1) with a compound represented by the following general formula (I-2) to obtain a compound represented by the following general formula (II), and c) A step of deprotecting the compound represented by the general formula (II) to obtain the compound represented by the general formula (III).

In formulas (I), (I-1), and (II), R _A ^1a and R _A ^1b each independently represent a protecting group for an amino group, or one of them represents a hydrogen atom, and the other represents amino. R _A ^1a and R _A ^1b each represent a protecting group of a group, or R _A ^1a and R _A ^1b represent a cyclic protecting group which is bonded to each other to form a ring together with the nitrogen atom of the amino group. The protecting group is preferably a protecting group that can be deprotected without using a heavy metal catalyst. The types of the protective group represented by R _A ^1a and/or R _A ^1b can be exemplified by being classified into, for example, the following (A) to ( _D ), but are not limited thereto.

(A) Protecting group having structure represented by Si(R ¹ ) ₃ (trialkylsilyl group)
When R _A ^1a and R _A ^{1b in the} general formulas (I), (I-1), and (II) each independently represent a protecting group for an amino group, and one of them is a hydrogen atom and the other is an amino group. when indicating the protecting _group, ^{R a 1a} and / or _R ^{a 1b} can be a Si protecting group of the structure represented by ^(R _{1) 3} (trialkylsilyl group).
In the structure represented by Si(R ¹ ) ₃ above, R ¹ is independently a straight chain having 1 to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon group having 3 to 6 carbon atoms. is there. Alternatively, R ¹ may be bonded to each other to form a 3- to 6-membered ring with the silicon atom to which they are bonded. Specific examples of R ¹ include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group. , Cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. In addition, when R ¹ 's are bonded to each other to form a ring with a silicon atom, groups in which one hydrogen atom is eliminated from these groups and the like can be mentioned.
Specific preferred examples of the protective group having a structure represented by Si(R ¹ ) ₃ include, but are not limited to, a trimethylsilyl group, a triethylsilyl group, and a tert-butyldimethylsilyl group.

( _A ) Protecting group having a structure represented by R _A ⁶ OCO R _A ^1a and R _A ^{1b in the} general formulas (I), (I-1), and (II) are independently amino-protecting groups. And when one represents a hydrogen atom and the other represents an amino-group protecting group, R _A ^1a and/or R _A ^1b may be a protecting group having a structure represented by R _A ⁶ OCO.
In the structure represented by R _A ⁶ OCO, R _A ⁶ is a monovalent hydrocarbon residue having 1 to 20 carbon atoms, and the residue is a halogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, It may contain a silicon atom, a phosphorus atom or a boron atom.
Examples of the protecting group represented by the structure of R _A ⁶ OCO include a methyloxycarbonyl group, an ethyloxycarbonyl group, an isobutyloxycarbonyl group, a tert-butyloxycarbonyl group, a tert-amyloxycarbonyl group, and 2,2,2-trichloro. Ethyloxycarbonyl group, 2-trimethylsilylethyloxycarbonyl group, phenylethyloxycarbonyl group, 1-(1-adamantyl)-1-methylethyloxycarbonyl group, 1,1-dimethyl-2-haloethyloxycarbonyl group, 1 , 1-dimethyl-2,2-dibromoethyloxycarbonyl group, 1,1-dimethyl-2,2,2-trichloroethyloxycarbonyl group, 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl group, 1-(3
5-di-t-butylphenyl)-1-methylethyloxycarbonyl group, 2-(2′-pyridyl)ethyloxycarbonyl group, 2-(4′-pyridyl)ethyloxycarbonyl group, 2
-(N,N-dicyclohexylcarboxamido)ethyloxycarbonyl group, 1-adamantyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group,
1-isopropyl allyloxycarbonyl group, cinnamyloxycarbonyl group, 4-
Nitrocinnamyloxycarbonyl group, 8-quinolyloxycarbonyl group, N-hydroxypiperidinyloxycarbonyl group, alkyldithiocarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group , P-bromobenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, 2,4-dichlorobenzyloxycarbonyl group, 4-methylsulfinylbenzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, diphenylmethyloxycarbonyl group , 9-fluorenylmethyloxycarbonyl group, 9-(2,7-dibromo)fluorenylmethyloxycarbonyl group, 2,7-di-t-butyl-[9-(10
, 10-Dioxo-thioxanthyl)]methyloxycarbonyl group, 4-methoxyphenacyloxycarbonyl group, 2-methylthioethyloxycarbonyl group, 2-methylsulfonylethyloxycarbonyl group, 2-(p-toluenesulfonyl)ethyloxycarbonyl group. Group, [2-(1,3-dithianyl)]methyloxycarbonyl group, 4-methylthiophenyloxycarbonyl group, 2,4-dimethylthiophenyloxycarbonyl group, 2-
Phosphonioethyloxycarbonyl group, 2-triphenylphosphonioisopropyloxycarbonyl group, 1,1-dimethyl-2-cyanoethyloxycarbonyl group, m-chloro-p-acyloxybenzyloxycarbonyl group, p-(dihydroxyboryl) Benzyloxycarbonyl group, 5-benzisoxazolylmethyloxycarbonyl group, 2-(trifluoromethyl)-6-chromonylmethyloxycarbonyl group, phenyloxycarbonyl group, m-nitrophenyloxycarbonyl group, 3,5 -Dimethoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, 3,4-dimethoxy-6-nitrobenzyloxycarbonyl group, phenyl(o-nitrophenyl)methyloxycarbonyl group and the like can be exemplified, but these are not limitative. Not done. Of these, a tert-butyloxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group, an allyloxycarbonyl group, a benzyloxycarbonyl group and a 9-fluorenylmethyloxycarbonyl group are preferable.

(C) Cyclic Protecting Group When R _A ^1a and R _A ^1b are cyclic protecting groups which are bonded to each other to form a ring with the nitrogen atom of the amino group, such cyclic protecting groups include N-phthaloyl group, N -Tetrachlorophthaloyl group, N-4-nitrophthaloyl group, N-dithiasucciloyl group, N-2,3-
Diphenyl maleoyl group, N-2,5-dimethylpyrrolyl group, N-2,5-bis(triisopropylsiloxy)pyrrolyl group, N-1,1,3,3-tetramethyl-1,3-disilaiso Examples include indoyl group, 3,5-dinitro-4-pyridonyl group, 1,3,5-dioxazinyl group, 2,2,5,5-tetramethyl-2,5-disila-1-azacyclopentane and the like. However, it is not limited thereto. Among them, N-phthaloyl group is preferable.

(D) Other protecting groups When R _A ^1a and/or R _A ^1b is a protecting group other than the above (a) to (c), examples of such protecting groups include a benzyl group and a p-methoxybenzyl group. , P-toluenesulfonyl group, 2-nitrobenzenesulfonyl group, (2-trimethylsilyl)ethanesulfonyl group, allyl group, pivaloyl group, methoxymethyl group, di(4-methoxyphenyl)methyl group, 5-dibenzosuberyl group, trinylmethyl Group, (4-methoxyphenyl)diphenylmethyl group, 9
Examples thereof include a phenylfluorenyl group, a [2-(trimethylsilyl)ethoxy]methyl group, and an N-3-acetoxypropyl group, but the protecting groups are not limited to these. Preferably, a protecting group that can be deprotected without using a heavy metal catalyst can be appropriately selected and used.
Of these, a benzyl group, a p-toluenesulfonyl group, a 2-nitrobenzenesulfonyl group, and an allyl group are preferable.

In the general formulas (I), (I-1), (II), and (III), R _A ² has 1 to 1 carbon atoms.
It is a straight-chain C6, or a branched or cyclic divalent hydrocarbon group having 3 to 6 carbon atoms. _RA ²
As specific examples of, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, Examples thereof include a group in which one hydrogen atom is eliminated from each of the cyclopentyl group and the cyclohexyl group.

In the general formulas (I), (I-1), (II), and (III), R _A ³ may include a single bond or a hetero atom such as a nitrogen atom, an oxygen atom, or a sulfur atom. 1 to 20 carbon atoms
Is a linear or branched or cyclic divalent hydrocarbon group having 3 to 20 carbon atoms. _RA ³
As specific examples of, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, cyclopentyl group, hexyl group,
Cyclohexyl group, octyl group, decyl group, dodecyl group, phenyl group, 0-tolyl group, m
-Tolyl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, 2,6-xylyl group, 3,4-xylyl group, 3,5-xylyl group , A group in which one hydrogen atom is eliminated from each of the mesityl group and the like. In these hydrocarbon groups, a part of carbon atoms may be substituted with a hetero atom such as a nitrogen atom, an oxygen atom, or a sulfur atom (provided that in the general formula (I), oxygen constituting O ⁻ M ⁺ is included). The bonding part with an atom is a bonding part with an oxygen atom constituting (OR _A ⁵ ) in the general formulas (I-1), (II), and (III)). Among them, R _A ³ preferably has a structure represented by the following general formula (VII). This is because in step a), the compatibility between the polymerization initiator represented by the general formula (I) and the polymerization solvent is improved.
^{_{- (OR A 5) P -}} (VII)
In the general formula _{(VII), R} ^{A 5} is the general formula (I-1), (I -2), (II),
And R _A ⁵ in (III), and specific examples thereof are as described later. p is 1 to
It is an integer of 10, and is preferably an integer of 1 to 5 and more preferably an integer of 1 to 2 from the viewpoint of purifying the alcohol compound as a raw material of the polymerization initiator by distillation.

Here, the total number of carbon atoms of R _A ² and R _A ³ described above is 4 or more. In addition, R
_When a part of carbon atoms in _A ³ is substituted with a hetero atom, the number of hetero atoms may be 4 or more in terms of the number of carbon atoms. The total number of carbon atoms of R _A ² and R _A ³ is preferably 4 to 15, more preferably 4 to 9. The above general formula (I)
In the polymerization initiator represented by, the chain length of the chain consisting of R _A ² and R _A ³ connecting the nitrogen atom at both ends and the oxygen atom (oxygen atom forming O ⁻ M ⁺ ) is 4 or more. By increasing the length, the solubility in the polymerization solvent is improved, and in the compound represented by the general formula (I), the transfer is prevented in the substrate where the protecting group on the nitrogen may be transferred to the oxygen. be able to.

In the general formulas (I-2), (II), and (III), R _A ⁴ is a hydrogen atom, or an optionally substituted linear, branched, or cyclic C 1-12 carbon atom. It is a hydrogen group, and the hydrocarbon group may contain a hetero atom. Specific examples of R _A ⁴ is methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, tert- butyl group, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexyl group, an octyl group ,
Decyl group, dodecyl group, phenyl group, 0-tolyl group, m-tolyl group, p-tolyl group, 2,
3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, 2,6-xylyl group, 3,
4-xylyl group, 3,5-xylyl group, mesityl group, vinyl group, allyl group and the like can be mentioned. When R _A ⁴ has a substituent, examples of the substituent include acetalized formyl group, cyano group, formyl group, carboxyl group, amino group, alkoxycarbonyl group having 1 to 6 carbon atoms, and 2 to 7 carbon atoms. Of the same or different tri(alkyl having 1 to 6 carbons) siloxy group, siloxy group, silylamino group, maleimide group, thiol group, hydroxyl group, methacryloyloxy group, acryloyloxy group, active ester group, and azido group. Can be mentioned. Specific examples of R _A ⁴ having a substituent include those represented by the following structural formulas, but the present invention is not limited thereto. In addition, the following formula shows the terminal part of R _A ⁴ of the substituted structure, and the dotted line in the formula shows that the hydrocarbon part of R _A ⁴ can take the variations as exemplified above. The number of substituents is not particularly limited, but is preferably 1 to 3. Such a substituent may be further protected with any appropriate protecting group.

The general formula (I-1), (I -2), in (II), and _{(III), R} ^{A 5} is an alkylene group having 2 to 8 carbon atoms. Especially, it is preferable that it is a C2-C3 alkylene group. That is, R _A ⁵ is preferably an ethylene group or a propylene group. In the general formulas (I-1), (I-2), (II), and (III), the (OR _A ⁵ ) unit is 1
It may be composed of only one kind of oxyalkylene group, for example, an oxyethylene group or an oxypropylene group, or two or more kinds of oxyalkylene groups may be mixed. When two or more oxyalkylene groups are mixed, (OR _A ⁵ ) may be a random polymer of two or more different oxyalkylene groups or a block polymer.

In the above general formulas (I) and (I-1), M represents an alkali metal. Specific examples of M include lithium, sodium, potassium, cesium, and a sodium-potassium alloy.

In the general formula (I-1), r represents, for example, an integer of 1 to 445, and preferably 10 to 3
It is an integer of 95, more preferably an integer of 20 to 345.

In the general formula (I-2), k is an integer of 0 to 5, for example. When k is 0, the compound represented by the general formula (I-2) may have a low boiling point and may be difficult to handle, or may have high toxicity. Therefore, k is preferably an integer of 1 to 5, More preferably, it is an integer of 1 to 3.

In general formula (I-2) above, L represents a leaving group. Specific examples of L include Cl, Br, I,
Examples thereof include, but are not limited to, trifluoromethane sulfonate (hereinafter referred to as TfO), p-toluene sulfonate (hereinafter referred to as TsO), methane sulfonate (hereinafter referred to as MsO), and the like.

In the general formulas (II) and (III), n represents an integer of 1 to 450, preferably 1
It is an integer of 0 to 400, more preferably an integer of 20 to 350. n is the above r and k
It is also expressed as the sum of.

The general formulas (I), (I-1), and (I-2) used in each step of the manufacturing method of the first embodiment are used.
), and (II) in the selection of each compound represented by the general formula (I), (I) -1), (
I-2), and during (II), desired _{^{R A 1a, R A 1b,}} R A 2, R A 3, R A
⁴ , R _A ⁵ , M, r, k, L, and n can be selected.

In addition, the present Embodiment 1 has, as an optional step, a pre-step for synthesizing the compound represented by the general formula (I) used as a polymerization initiator before the steps a) to c). You may have. In this pre-step, a step of synthesizing a compound represented by the following general formula (i) used as a precursor of a polymerization initiator (pre-step 1) and a compound represented by the general formula (i) are used. It includes a step (previous step 2) of synthesizing the compound represented by the general formula (I) used as a polymerization initiator. In the present embodiment, as a pre-process, the pre-process 1 is followed by the pre-process 2,
A mode in which only the previous step 2 is performed without going through the previous step 1 is also included. The scheme of the previous step 2 is shown below.

（上記一般式（ｉ）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＭは、上記一般式（
Ｉ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、Ｒ_Ａ ^３、及びＭと同一である。）

(In the above general formula (i), R _A ^1a , R _A ^1b , R _A ² , R _A ³ and M are each represented by the above general formula (
_R ^A 1a in ^{_{I), R A 1b, R}} A 2, R A 3, and is identical to M. )

In addition, Embodiment 1 has a post-treatment step of purifying the compound represented by the general formula (III) obtained in step c) as an optional step after steps a) to c). It may be.

In the following description of the embodiments, the previous steps 1 and 2, steps a) to c), and
The post-processing steps will be described in this order.

[Previous step 1]
The previous step 1 is a step of synthesizing an alcohol compound represented by the above general formula (i) used as a precursor of a polymerization initiator, and its production may be performed, for example, in the following step (i-1). However, the invention is not limited to this.

（上記一般式（ｉａ）及び（ｉｂ）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、及びＲ_Ａ ^３は上記
一般式（ｉ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、及びＲ_Ａ ^３と同一である。すなわち、上
記一般式（Ｉ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ_Ａ ^２、及びＲ_Ａ ^３と同一である。Ｌ^１は脱離
基を表す。）

(In the general formulas (ia) and (ib), R _A ^1a , R _A ^1b , R _A ² and R _A ³ are R _A ^1a , R _A ^1b , R _A ² in the general formula (i), And R _A ^3. That is, they are the same as R _A ^1a , R _A ^1b , R _A ² and R _A ^{3 in the} general formula (I), and L ¹ represents a leaving group.).

In the above general formulas (ia) and (ib), specific examples of the leaving group for L ¹ include Cl, Br and I.
, TfO, TsO, MsO, and the like, but are not limited thereto.

When performing the step (i-1) to synthesize the compound represented by the general formula (i),
For example, a basic compound may be added to the compound represented by the general formula (ia) without a solvent, and then the compound represented by the general formula (ib) may be added dropwise and the mixture may be reacted to cause a reaction. Alternatively, the compound represented by the general formula (ia) may be dissolved in another solvent, the basic compound may be added thereto, and then the compound represented by the general formula (ib) may be added dropwise and mixed to react. General formula (ib)
The amount of the compound represented by is, for example, 1 to 5 times, preferably 1.5 to 3 times the amount of moles of the compound represented by the general formula (ia), and optionally amino. From the viewpoint of reacting the protecting group with only the group, 1.5 to 2 times the amount is more preferable.

When a solvent is used in the step (i-1), specific examples of the solvent include THF and 1
, Ethers such as 4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogens such as methylene chloride, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile and acetone. However, the present invention is not limited to these. The amount of the solvent used is not particularly limited, but is, for example, 1 to 20 times, preferably 2 to 10 times, and more preferably 2 to 5 times the mass of the compound represented by the general formula (ia). Is the amount.

Specific examples of the basic compound used in the step (i-1) include hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, and carbonates such as sodium carbonate, potassium carbonate and cesium carbonate. Salts, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, metal hydrides such as sodium hydride and potassium hydride, primary, secondary and tertiary aliphatic amines , Mixed amines, aromatic amines, heterocyclic amines, aqueous ammonia, and the like, but are not limited thereto. The amount of the basic compound used is, for example, 1 to 5 times, preferably 1.5 to 3 times, and more preferably 1.5 to 2 times the mol number of the compound represented by the general formula (ia).
It is double amount.

The reaction temperature in the step (i-1) can be carried out within the range of the melting point to the boiling point of the solvent used, and is, for example, -60°C to 150°C, preferably 0°C to 80°C. The reaction of the step (i-1) can be terminated when the compound represented by the general formula (ia) disappears by gas chromatography or when the general formula (i) is obtained as a main product. ..

When R _A ^1a and R _A ^1b are to be different protecting groups, or when the protecting group has a high steric hindrance and a protecting group is simultaneously applied to not only the amino group but also the hydroxy group, the amino group is first selected. Is protected with a first protecting group, then the hydroxy group is protected with another protecting group capable of deprotection, followed by protection of the amino group with a second protecting group, and finally deprotection of the hydroxy group. Can be synthesized. Also, depending on the reaction conditions, selectivity between the amino group and the hydroxy group may not be obtained, and the hydroxy group may be protected, or only one protecting group may be introduced into the amino group. In that case, The compound represented by the general formula (i) and other by-products can be separated by precision distillation. Further, the compound represented by the general formula (i) is preferably purified by distillation to remove water even when a by-product is not formed. In that case, the general formula (i
The water content of the compound represented by () is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less.

When the compound represented by the general formula (i) contains a hetero atom in R _A ³ , another method for producing the compound represented by the general formula (i) is, for example, next to the hetero atom represented by R _A ^3. Examples thereof include, but are not limited to, the following methods (i-2) to (i-3) using a compound represented by the general formula (if) having a hydrogen atom.

（上記一般式（ｉｃ）、（ｉｄ）、（ｉｅ）、及び（ｉｆ）中、Ｒ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ
_Ａ ^２、Ｒ_Ａ ^３、及びＬ^１は上記一般式（ｉａ）及び（ｉｂ）中のＲ_Ａ ^１ａ、Ｒ_Ａ ^１ｂ、Ｒ
_Ａ ^２、Ｒ_Ａ ^３、及びＬ^１と同一である。Ｌ^２は脱離基を表す。）

(In the above general formulas (ic), (id), (ie), and (if), R _A ^1a , R _A ^1b , R
_A ² , R _A ³ and L ¹ are R _A ^1a , R _A ^1b and R in the above general formulas (ia) and (ib).
It is the same as _A ² , R _A ³ , and L ¹ . L ² represents a leaving group. )

In the above general formulas (ic) and (ie), specific examples of the leaving group for L ² include Cl, Br, I,
Examples include, but are not limited to, TfO, TsO, MsO, and the like.

When carrying out the above step (i-2), for example, a basic compound is added to the compound represented by the general formula (ic) without a solvent, and then the compound represented by the general formula (id) is added dropwise. Alternatively, the compound represented by the general formula (ic) may be dissolved in a suitable solvent and the basic compound may be added after the compound represented by the general formula (ic) is dissolved in a suitable solvent. You may make it react by dropping and mixing. The amount of the compound represented by the general formula (id) is calculated by the general formula (ic)
In an amount of, for example, 2 to 10 times, preferably 2 to 5 times the number of moles of the compound represented by
More preferably, the amount is 2 to 3 times.

When a solvent is used in the above step (i-2), specific examples of the solvent include the above step (i-1).
The same as the specific examples of the solvent described in (). The amount of the solvent used is not particularly limited, but is, for example, 1 to 20 times, preferably 2 to 10 times, and more preferably 2 to 5 times the mass of the compound represented by the general formula (ic). Is.

Specific examples of the basic compound used in the step (i-2) are the same as the specific examples of the basic compound described in the step (i-1). The amount of the basic compound used is determined by the formula (i)
The amount is, for example, 2 to 10 times, preferably 2 to 5 times, and more preferably 2 to 3 times the mol number of the compound represented by c).

The reaction temperature in the step (i-2) can be carried out within the range of the melting point to the boiling point of the solvent used, and is, for example, -60°C to 150°C, preferably 0°C to 80°C. The reaction may be terminated when the compound represented by the general formula (ic) disappears by gas chromatography or when the compound represented by the general formula (ie) is obtained as a main product.

Then, when performing the step (i-3) to synthesize the compound represented by the general formula (i), the compound of the general formula (if) is added to the reaction solution after the step (i-2) is completed. The compound represented by the formula (1) and the basic compound may be added directly, or once the compound represented by the formula (ie) is purified and taken out, the compound represented by the formula (if) and the base are added. It may be added dropwise to the mixed solution of the organic compound and the solvent. Further, the step (i-3) can be carried out without a solvent. The amount of the compound represented by the general formula (if) used is 1 to 3 with respect to the number of moles of the compound represented by the general formula (ie).
The amount is 0 times, preferably 2 to 20 times, and more preferably 5 to 10 times. For example R _A ³
Is a compound represented by the general formula (VII), the compound represented by the general formula (if) is a diol, but the compound represented by the general formula (if) is represented by the general formula (ie). By using an excessive amount with respect to the number of moles of the compound represented, one terminal hydroxy group of the compound represented by the general formula (if) can be reacted.

When a solvent is used in the step (i-3), specific examples of the solvent are the above step (i-1).
It is the same as the specific example of the solvent described in. The amount of the solvent used is not particularly limited, but is, for example, 1 to 20 times, preferably 2 to 10 times, and more preferably 2 to 5 times the mass of the compound represented by the general formula (ie). Is. Specific examples of the basic compound used in the step (i-3) are the same as the specific examples of the basic compound described in the step (i-1). The amount of the basic compound used is, for example, 1 to 1 with respect to the number of moles of the compound represented by the general formula (ie).
The amount is 2 times, preferably 1 to 1.5 times, and more preferably 1 to 1.2 times.

The reaction temperature in the step (i-3) can be carried out within the range of the melting point to the boiling point of the solvent used, and is, for example, -60°C to 150°C, preferably 0°C to 80°C. The reaction can be terminated when the compound represented by the general formula (ie) disappears by gas chromatography. Depending on the reaction conditions, both the heteroatom on R _A ³ and the terminal hydroxy group may react with the compound represented by the general formula (ie) to produce a by-product. The compound represented by (i) and the by-product can be separated. Also,
The compound represented by the general formula (i) is preferably purified by distillation to remove water even when a by-product is not formed. In that case, the water content of the compound represented by the general formula (i) is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less.

[Previous step 2]
The previous step 2 is a step of reacting the compound represented by the general formula (i) with an alkali metal or an alkali metal compound to obtain the compound represented by the general formula (I).

In the previous step 2, the alkali metal or the alkali metal compound to be reacted with the compound represented by the general formula (i) is an alkali metal represented by M, a hydride of an alkali metal represented by M ⁺ H ⁻ , R _{^{X - M +, [R Y}} ] · - M organic alkali metal _{(R X} represented by the ⁺ represents an alkyl group having 1 to 20 carbon atoms that may have a substituent, preferably 1 carbon atoms represents an 20 alkyl group or an arylalkyl group having 7 to 20 carbon atoms of, R _Y represents an even aromatic compound has a substituent), and R _Z O ^- M ⁺ monovalent represented Alkali metal salt of alcohol (
R _Z represents a substance selected from the group consisting of C 1-6 alkyl groups).

Specific examples of the alkali metal of M include lithium, sodium, potassium, cesium, and a sodium-potassium alloy. Specific examples of M ⁺ H ⁻ include sodium hydride, potassium hydride and the like. R _X ^- Examples of M ^+, ethyllithium, sodium ethyl, n- butyl lithium, sec- butyl lithium, ter
t-Butyllithium, 1,1-diphenylhexyllithium, 1,1-diphenyl-3-
Methyl pentyl lithium, 1,1-diphenylmethyl potassium, cumyl sodium, cumyl potassium, cumyl cesium and the like can be mentioned. [R _Y] ^{· -} Examples of M ^+, lithium naphthalenide, sodium naphthalenide, potassium naphthalenide, Ann Toresen lithium, anthracene sodium, anthracene potassium, sodium biphenyl,
Sodium 2-phenylnaphthalenide, sodium phenanthrene, sodium acenaphthylenide, sodium benzophenone ketyl, sodium 1-methylnaphthalenide, potassium 1-methylnaphthalenide, sodium 1-methoxynaphthalenide, potassium 1-methoxynaphthalene Examples thereof include lenide, and these compounds can be used alone or in combination of two or more. R _Z O ^- Examples of _{R Z} in M ^+, methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, sec- butyl group, te
Examples include rt-butyl group, n-pentyl group, isopentyl group, n-hexyl group,
It is not limited to these. Among them, the alkali metal or the alkali metal compound is preferably sodium, potassium, sodium hydride or potassium hydride from the viewpoint of suppressing side reactions, and sodium naphthalenide or potassium naphthalate from the viewpoint of high reactivity. Lenide, sodium anthracene, potassium anthracene, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide are preferred.

The amount of the alkali metal or alkali metal compound used in the reaction of the previous step 2 is
0.5 to 3.0 equivalents, preferably 0, relative to the number of moles of the compound represented by the above general formula (i).
． It is 8 to 2.0 equivalents, more preferably 0.9 to 1.0 equivalents. In particular, when an alkali metal compound that can also function as a polymerization initiator is used in step a), the amount used should be 1.0 equivalent or less. For example, when potassium methoxide is used, it is necessary to prevent the potassium methoxide from functioning as a polymerization initiator in step a) by distilling off the methanol produced in the previous step 2 under reduced pressure after the synthesis of the polymerization initiator. There is.

In the previous step 2, when synthesizing the compound represented by the above general formula (I), for example, after dissolving the compound represented by the general formula (i) distilled and purified in the previous step 1 in an appropriate solvent The alkali metal or the alkali metal compound may be added directly, or the compound represented by the general formula (i) may be added after the alkali metal or the alkali metal compound is dissolved in a suitable solvent. Specific examples of the solvent used in the previous step 2 include, but are not limited to, ethers such as THF and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. .. When a solvent is used, it is preferable to use one that has been distilled using a dehydrating agent such as sodium metal. The water content of the solvent is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less. The amount of the solvent used is not particularly limited, but is, for example, 1 to 50 times the amount of the compound represented by the general formula (i),
The amount is preferably 2 to 10 times, more preferably 2 to 5 times. The reaction in the previous step 2 is carried out at a temperature of −78 to 100° C., preferably 0° C. to the reflux temperature of the solvent used (eg, 0° C. to TH).
The reflux temperature of F is 66° C.), and the reaction system can be cooled or heated as necessary.

Above all, as the solvent used in the previous step 2, it is preferable to use the same solvent as the solvent used as the polymerization solvent in the step a) described later. This is because whether or not the polymerization initiator synthesized in the previous step 2 is soluble in the polymerization solvent used in the step a) can be confirmed in advance during the synthesis of the polymerization initiator in the previous step 2. Specifically, for example, THF is used as a reaction solvent in the previous step 2.
When potassium hydride (eg, 1.0 equivalent or less potassium hydride with respect to the compound represented by the general formula (i) above) is used as the alkali metal compound and THF is used as the polymerization solvent in step a), The solubility of the polymerization initiator in the polymerization solvent can be confirmed as follows. The reaction in the previous step 2 progresses, powdery potassium hydride is reduced, and hydrogen is generated. The polymerization initiator represented by the general formula (I) generated at this time does not precipitate in THF which is the reaction solvent in the previous step 2, and when the potassium hydride is finally reacted, the reaction solution The solubility of the polymerization initiator in the subsequent step a) in the polymerization solvent can be confirmed in advance by confirming whether there is no precipitation of salt or cloudiness therein.

Further, as another method for confirming the solubility of the polymerization initiator represented by the general formula (I) in the polymerization solvent used in step a) in advance, the following method can be exemplified, but the method is not limited thereto. As described above, the compound represented by the general formula (i) is reacted with the alkali metal or the alkali metal compound to synthesize the polymerization initiator represented by the general formula (I), and then the compound represented by the general formula (I) is represented. The solvent and reagents other than the above polymerization initiator are removed by a conventional method to take out the polymerization initiator represented by the general formula (I). The obtained polymerization initiator represented by the general formula (I) was dissolved in a polymerization solvent used in the subsequent step a) at a concentration of, for example, 20 wt%, and whether salt precipitation or cloudiness was visually observed. You can check.

As described above, when the polymerization initiator is prepared in a state where the monohydric alcohol, which is the raw material of the polymerization initiator, contains water and the polymerization with the alkylene oxide is performed using the polymerization initiator, the diol polymer is a by-product. To do. It is extremely difficult to separate the diol polymer from the target substance, and if the diol polymer or a polymer containing impurities derived therefrom is used as it is, the desired performance of the polymer micelle agent may not be obtained. Therefore, when carrying out the polymerization reaction in the subsequent step a), it is preferable to keep the water content of the reaction system containing the compound (polymerization initiator) represented by the general formula (I) as low as possible. In this regard, the compound represented by the above general formula (i), which is a precursor of the compound represented by the general formula (I), has, for example, R _A ^1a =R _A ^1b =triethylsilyl group, R _A ² =CH ₂ CH ₂ CH _2, when the ^{_{R a 3 = OCH 2 CH 2}} , boiling point of 120 ° C.
Since it is as high as (10 Pa) and the boiling point difference with water is sufficient, it is possible to separate water by performing reduced pressure drying. Therefore, before the reaction of the compound represented by the general formula (i) with the alkali metal or the alkali metal compound in the previous step 2, the compound represented by the general formula (i) is sufficiently dried under reduced pressure. It is preferable to carry out distillation after the above. General formula (i) after distillation
The water content of the compound represented by is, for example, 50 ppm or less, preferably 10 ppm or less, and more preferably 5 ppm or less. When the compound represented by the general formula (i), which is a raw material of the polymerization initiator, is kept in a water-free state as described above, a diol polymer is used when a polymerization reaction is performed using the obtained polymerization initiator. The by-product of can be better suppressed.

The substance amount of the raw material alcohol represented by the general formula (i) used in the previous step 2 and the previous step 2
From the total weight of the reaction solution after completion, the concentration (mmol/g) of the substance that can act as a polymerization initiator in the reaction solution after completion of the previous step 2 (reaction solution after synthesis of the polymerization initiator) is determined. be able to. That is, the concentration of the substance capable of functioning as a polymerization initiator in the reaction solution after the completion of the preceding step 2 is defined as "the amount of the substance alcohol (i) used (mmol)/the weight of the entire reaction solution after the completion of the preceding step 2". Sa (g)". In the reaction solution after completion of the previous step 2, the general formula (i
This is because, when the raw material alcohol represented by) remains, the raw material alcohol also acts as a polymerization initiator. Since the reaction in (the next step a) is an equilibrium reaction, the polymer terminal alkoxide generated by the reaction of the compound represented by the general formula (I) as a polymerization initiator withdraws the proton of the raw material alcohol (i), and the alkoxide (polymerization Act as an initiator). However, as described later, it is desirable that the residual amount of the raw material alcohol in the reaction solution after the completion of the previous step 2 is as small as possible. The reaction solution after completion of the previous step 2 can be used as it is as a polymerization initiator solution in the subsequent step a).

Sodium salt and potassium salt, which are commonly used polymerization initiators, are THF.
It is often not dissolved alone in a polymerization solvent such as. In that case, in order to carry out uniform polymerization, it is necessary to leave an excessive amount of alcohol as a raw material for the initiator (for example, in Patent Document 4, 13 mol of methanol to 2 mol of sodium methoxide as a polymerization initiator). However, when these alcohols are present in the reaction system, a decrease in the polymerization rate is unavoidable, and severe reaction conditions such as high temperature and high pressure are required to increase the polymerization rate. On the other hand, the alcohol derivative represented by the general formula (I), which is used as the polymerization initiator in the present embodiment and whose amino group is protected by a protecting group, has a structure similar to that of the polymerization solvent in its internal structure. It is easily soluble in the polymerization solvent. For example, when R _A ³ has an oxyethylene structure, the compound represented by the general formula (I) is easily soluble in ether compounds including THF and diethylene glycol dimethyl ether. Therefore, it is not necessary to leave the initiator raw material alcohol in order to dissolve the polymerization initiator in the polymerization solvent. Therefore, the polymerization rate is improved, and the polymerization can be performed under mild conditions.

Thus, in order to obtain a sufficient reaction rate under mild conditions in the next step a), it is preferable to synthesize a polymerization initiator having a small residual amount of the starting material alcohol in the previous step 2. Specifically, a polymerization initiator represented by the general formula (I) after synthesizing a polymerization initiator represented by the general formula (I) from the starting material alcohol represented by the general formula (i), The substance amount ratio of the starting material alcohol represented by the general formula (i) is preferably 100:0 to 80:20 (mol%), and more preferably 100:0 to 90:10 (mol%). To react. For that purpose, the number of moles of the alkali metal or the alkali metal compound used in the previous step 2 is 0.8 to 1.5, preferably 0.9 to 1.0 of the compound represented by the general formula (i). It is preferable to carry out under such conditions.

In addition, after synthesizing the polymerization initiator represented by the above-mentioned general formula (I), the starting material alcohol represented by the general formula (i) can be distilled off under reduced pressure from the reaction system. In that case, the substance amount ratio of the polymerization initiator represented by the general formula (I) and the starting material alcohol represented by the general formula (i) after completion of the previous step 2 is 100:0 to 98:2 (mol). %), and it is more preferable to remove the raw material alcohol until it becomes 100:0 to 99:1 (mol %). By reducing the residual amount of the raw material alcohol, the polymerization rate in the next step a) can be further increased.

In this embodiment, as described above, the initiator raw material alcohol compound represented by the general formula (i), which is a factor for improving the solubility of the polymerization initiator in the polymerization solvent and a factor for decreasing the polymerization rate, does not remain. In both cases, the compound represented by the general formula (I), which is an initiator, can be dissolved in a polymerization solvent. The structure that plays the role is R _A ³ in the general formula (I), and for example, the polymerization solvent is TH.
In the case of F, preferably R _A ³ is a structure represented by the above-mentioned general formula (VII) ((OR _A ⁵
) _P ), the compatibility between the polymerization initiator and the polymerization solvent is increased, and the polymerization initiator can be dissolved in the polymerization solvent without the substantial presence of the starting material alcohol. As a result, it is possible to polymerize in a uniform system, and it is possible to synthesize the narrowly dispersed polyalkylene glycol derivative under mild conditions.

[Step a)]
Step a) is a step of reacting the compound (polymerization initiator) represented by the general formula (I) with an alkylene oxide in a polymerization solvent. According to step a), the compound represented by the following general formula (I-1) can be obtained.

In step a), preferably, the compound represented by the general formula (I) is completely dissolved in the polymerization solvent and then reacted with alkylene oxide. As described above, the compound represented by the general formula (I) is easily soluble in the polymerization solvent even when the compound represented by the general formula (i), which is the starting alcohol, is not substantially present. Among them, from the viewpoint of high compatibility with the polymerization solvent, R _A ³ in the general formula (I) is an alkylene oxide structure represented by the general formula (VII) (-(OR _A
⁵ ) It is preferable to have _P − ). The fact that the compound represented by the general formula (I) can be completely dissolved in the polymerization solvent can be confirmed, for example, by visual observation by the absence of salt precipitation or clouding in the polymerization solvent. At this time, it is desirable that salt precipitation or clouding is not observed when the mass of the polymerization solvent is 10 times or less (and 1 time or more) the mass of the compound represented by the general formula (I). That is, a compound represented by the general formula (I) in a polymerization solvent solution containing a compound represented by the general formula (I)
The concentration of the compound represented by () is preferably 9.1% by weight or more (and 50% by weight or less), and it is desirable that salt precipitation or clouding is not observed. After confirming that the compound represented by the general formula (I) was completely dissolved in the polymerization solvent as described above, the concentration of the general formula (
A polymerization solvent solution containing the compound represented by I) may be used in the polymerization reaction, or may be used in the polymerization reaction in a state of being diluted by further adding the polymerization solvent. The amount of the polymerization solvent may be adjusted to, for example, 1 to 50 times, preferably 2 to 25 times the amount of the alkylene oxide used at the start of the polymerization reaction.

Further, as described above, the presence of the raw material alcohol causes a decrease in the polymerization rate.
In (), it is preferable to use the polymerization initiator in a state where the raw material alcohol is small. For example, when the above-mentioned pre-step 2 is carried out before step a), it is obtained in the pre-step 2, preferably 10
A reaction product containing a polymerization initiator represented by the general formula (I) and a raw material alcohol represented by the general formula (i) in a substance ratio of 0:0 to 80:20 (a reaction product containing a small amount of the raw material alcohol). ),
It is preferable to use it as it is by dissolving it in a polymerization solvent.

The polymerization solvent used in step a) has 4 carbon atoms from the viewpoint of high compatibility with the polymerization initiator.
Cyclic ether compounds of 10 to 10 and linear or branched ether compounds are preferably used. Specific examples of the cyclic ether compound include furan, 2,3-dihydrofuran, 2,
5-dihydrofuran, 2,3-dimethylfuran, 2,5-dimethylfuran, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 2
,5-dimethyltetrahydrofuran, 1,2-methylenedioxybenzene, 1,3-dioxolane, 2-methyl-1,3-dioxolane, 4-methyl-1,3-dioxolane, 2,
2-dimethyl-1,3-dioxolane, 3,4-dihydro-2H-pyran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, 2,4-dimethyl-1,3-dioxane, 1,4 Examples thereof include, but are not limited to, benzodioxane, 1,3,5-trioxane, and oxepane. Specific examples of the linear or branched ether compound include, but are not limited to, monoethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and the like. Particularly THF is preferably used. It is also possible to use a polymerization solvent other than the ether compound, and specific examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc., but are not limited thereto. The polymerization solvent to be used may be a simple solvent or may be used in combination of two or more kinds, and in the case of combining, the combination of compounds and the mixing ratio thereof are not limited.

The amount of the polymerization solvent used in the polymerization reaction is not particularly limited, but is, for example, 1 to 50 times, preferably 2 to 30 times, and more preferably 3 to the mass of the alkylene oxide used.
20 times the amount. As the polymerization solvent, it is preferable to use a solvent that has been distilled using a dehydrating agent such as metallic sodium. The water content of the polymerization solvent is, for example, 50 ppm or less, preferably 1
It is 0 ppm or less, more preferably 5 ppm or less.

Specific examples of the alkylene oxide used include ethylene oxide and propylene oxide. Among them, ethylene oxide is preferable because it has high polymerizability. The ratio of the amount of the compound represented by the general formula (I) used in the polymerization reaction to the alkylene oxide is not particularly limited, but as the ratio of the amount of the compound represented by the general formula (I): the alkylene oxide, For example, it is 1:1 to 1:450, preferably 1:10 to 1:400.

In the step a), for example, the alkylene oxide may be added all at once to the reaction system in which the compound represented by the general formula (I) is dissolved in a polymerization solvent, or may be added sequentially. Alternatively, a solution prepared by dissolving alkylene oxide in the above-mentioned polymerization solvent may be added dropwise to the above reaction system. The polymerization can be carried out, for example, at a temperature of 30 to 80°C, preferably 50 to 80°C, more preferably 60 to 80°C. The pressure during the polymerization reaction is, for example, 1.0 MPa or less, preferably 0.5 MPa or less. The progress of the polymerization reaction can be monitored by GPC, and the time point at which the conversion of alkylene oxide does not change can be regarded as the end point. As described above, the present embodiment is advantageous in that it does not require severe reaction conditions such as high temperature and high pressure during the polymerization.

[Step b)]
Step b) is a step of reacting the compound represented by the general formula (I-1) obtained in step a) with the compound represented by the following general formula (I-2). According to the step b), the following general formula (
The compound represented by II) can be obtained.
R _A ⁴ (OR _A ⁵ ) _k L (I-2)

In the step b), when synthesizing the compound represented by the general formula (II), for example,
The compound represented by the general formula (I-2) may be directly added to the reaction solution (reaction solution containing (I-1)) after completion of the reaction in step a), or if necessary, it is suitable. The compound represented by the general formula (I-2) may be dissolved in another solvent before use. Specific examples of the solvent used include THF and 1
And ethers such as 4-dioxane, and aromatic hydrocarbons such as benzene, toluene and xylene. The amount of the solvent used is not particularly limited, but is, for example, 1 to 50 times, preferably 2 to 10 times, and more preferably 2 to 5 times the mass of the compound represented by the general formula (I-2). It is double amount. The reaction is carried out at a temperature of 0 to 100°C, preferably 40 to 70°C.
The reaction system can be cooled or heated as necessary. The general formula (I
The amount of the compound represented by -2) is, for example, 1 to 50 equivalents, preferably 1 to 40 equivalents, more preferably 1 to 30 with respect to the number of moles of the compound represented by the general formula (I-1). It is equivalent. The progress of the reaction can be monitored by ¹ H-NMR, and the time point when the peak derived from the hydroxyl group generated when the reaction solution is quenched with water disappears can be regarded as the end point.

The reaction of step b) proceeds without a catalyst, but can be accelerated by using a base catalyst. Examples of the base catalyst include hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, sodium methoxide, sodium ethoxide and potassium t-butoxide. , Metal alkoxides such as sodium hydride, metal hydrides such as potassium hydride, primary, secondary, tertiary aliphatic amines, mixed amines, aromatic amines, heterocyclic amines , Ammonia water, etc. can be used, but not limited thereto. The amount of the base catalyst used is, for example, 0.1 to 3 with respect to the number of moles of the compound represented by the general formula (I-1).
The amount is 0 times, preferably 1 to 20 times.

In step b), in order to separate the alkali metal salt formed by the reaction of the compound represented by general formula (I-1) and the compound represented by general formula (I-2), an alkali adsorbent May be further used. Suitable alkali adsorbents include aluminum hydroxide (for example, "Kyoward 200" manufactured by Kyowa Chemical Industry Co., Ltd.), synthetic hydrotalcide (for example, "Kyoward 500" manufactured by Kyowa Chemical Industry Co., Ltd.), synthetic magnesium silicate (for example, Kyowa Chemical Industry Co., Ltd.
Kyoward 600"), synthetic aluminum silicate (for example, "Kyoward 700" manufactured by Kyowa Chemical Industry Co., Ltd., aluminum oxide/magnesium oxide solid solution (for example, "KW-2000" manufactured by Kyowa Chemical Industry Co., Ltd.), manufactured by Tomita Pharmaceutical Co., Ltd. "Tomita AD700NS") is used,
It is not limited to these. Among them, KW-2000 is preferable because of its high ion-trapping ability. The amount of the alkali adsorbent used is 0.01 to the mass of the compound represented by the general formula (II).
The amount is 10 times, preferably 0.1 to 8 times, and more preferably 0.3 to 6 times, but is not particularly limited. The alkaline adsorbent includes a compound represented by the general formula (I-1) and a general formula (I
When the reaction with the compound represented by I-2) is completed, it may be directly added to the reaction solution, or the alkali metal salt formed after the completion of the reaction may be filtered and then added to the reaction solution. .. After the reaction, the reaction can be carried out for 0.5 to 6 hours and then the removal can be carried out by filtration, but the reaction time is not particularly limited. As a method for using the adsorbent, the adsorbent may be added and stirred in the reaction solution as a batch method, or the reaction solution may be passed through a column filled with the adsorbent as a column method. Specific examples of the solvent for the adsorption treatment include THF, ethers such as 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, ethyl acetate,
Esters such as n-butyl acetate, γ-butyrolactone, acetone, methyl ethyl ketone,
Examples thereof include ketones such as methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile and the like, but are not limited thereto. Aromatic hydrocarbons such as benzene, toluene, and xylene are preferable in order to enhance the salt adsorption ability. These solvents may be used alone or in combination of one kind or two or more kinds. In that case, the mixing ratio is not particularly limited.

When the compound represented by the general formula (II) is a solid, it can be taken out and used as a solid before proceeding to the next step c). In that case, the reaction liquid can be crystallized as it is or after being concentrated and then dropped into a poor solvent. Upon concentration, the concentration of the compound represented by the general formula (II) is, for example, 10 to 50% by mass, preferably 15 to 45% by mass, more preferably 20 to
It is adjusted to 40% by mass.

When concentrating, crystallization may be carried out by substituting a good solvent for the compound represented by the general formula (II) with a solvent. In this case, good solvents include THF, ethers such as 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, ethyl acetate, n-butyl acetate, γ-.
Esters such as butyrolactone, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (
Examples thereof include DMF) and acetonitrile, but are not limited thereto. These solvents may be used alone or in combination of one kind or two or more kinds. In that case, the mixing ratio is not particularly limited. The concentration of the compound represented by the general formula (II) after solvent substitution is, for example, 5 to 50% by mass, preferably 10 to 40% by mass, more preferably 10% by mass.
Is about 30% by mass.

As the poor solvent, one having a low solubility of the compound represented by the general formula (II) is used, and examples thereof include carbonization of hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. Hydrogen and ethers such as diethyl ether, diisopropyl ether and di-n-butyl ether are preferably used. The amount of the poor solvent used is not particularly limited, but is, for example, 5 to 5 with respect to the mass of the compound represented by the general formula (II).
The amount of the poor solvent is 100 times, preferably 5 to 50 times, and more preferably 5 to 20 times. The poor solvent may be used alone, or may be used as a mixture with another solvent. Other solvents to be mixed include esters such as ethyl acetate, n-butyl acetate and γ-butyrolactone, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, hydrocarbons such as benzene, toluene, xylene and cumene, and tetrahydrofuran. , Diethyl ether, ethers such as 1,4-dioxane, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol monomethyl ether, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile and the like. Yes, but not limited to.

In step b), after the solid is deposited by crystallization, the solid may be washed and purified if necessary. The solvent used for washing is preferably the same poor solvent as described above, but is not particularly limited including the amount of the washing solvent used. The compound represented by the general formula (II) can be taken out as a solid by drying the obtained solid under reduced pressure.

When water is mixed in during the polymerization of the alkylene oxide in the above step a), the diol derivative is formed as described above, and the diol derivative represented by the following general formula (VIII) is formed through the step b). To do.
R _A ⁴ (OR _A ⁵ ) _q OR _A ⁴ (VIII)
(In the general formula (VIII), R _A ⁴ and R _A ⁵ are as defined for the general formula (II), and are the same as R _A ⁴ and R _A ^{5 in} the general formula (II). It is an integer of 1 to 890.)

Since the diol derivative represented by the general formula (VIII) is produced when water acts as a polymerization initiator, it differs from the case where the polymerization initiator represented by the general formula (I) functions at both ends. The polymerization proceeds from. Therefore, q is about twice as large as r in the above general formula (I-1), and represents, for example, an integer of 1 to 890, preferably 20 to 790, and more preferably 40 to
690. In the present embodiment, it is possible to suppress the production of the diol derivative as described above, preferably by carrying out the polymerization reaction in a state where the water content in the reaction system is kept low as described above.

Further, in the conventional synthesis methods described in Patent Document 4 and Patent Document 5, since the polymerization end is converted into a cyanoethyl group and then an amino group, the diol impurity is finally derived to a compound having amino groups at both ends. However, since this compound has a terminal structure similar to that of the target compound, it cannot be separated by a purification method using a cation exchange resin as described later. On the other hand, in this embodiment, the diol derivative represented by the general formula (VIII) has a terminal structure different from that of the target compound represented by the general formula (III). Therefore, for example, it can be separated by purification using a cation exchange resin as described below, and as a result, a highly pure polyalkylene glycol derivative (III) having an amino group can be synthesized.

[Step c)]
In step c), the protecting group in the compound represented by the general formula (II) obtained in step b) is deprotected. This deprotection is preferably performed without the use of heavy metal catalysts. The heavy metal catalyst here is, for example, Co, Ni, Pd, Pt, Rh, Ru, Cu.
, A catalyst using a heavy metal such as Cr as a raw material. In the step c), deprotection without using a heavy metal catalyst is carried out, for example, by R _A ^1a and/or R _A ^{1 in the} general formula (II).
^{When b} is a silyl group (case (a) above), water or an alcohol (R ⁶ OH
Wherein R ⁶ is a hydrocarbon group having 1 to 5 carbon atoms) and the compound represented by the general formula (II) are reacted to convert into the compound represented by the general formula (III). be able to. Specific examples and amounts of the acid catalyst used are as described in Embodiment 2 below.

Further, for example, when R _A ^1a and/or R _A ^1b is a tert-butyloxycarbonyl group (in the case of (a) above), a strong acid such as trifluoroacetic acid or hydrochloric acid is represented by the above general formula (II). It can be deprotected by acting on the compound. The amount of these strong acids used is, for example, 0.01 to 1,000 equivalents, preferably 0, of the number of moles of the compound represented by the general formula (II).
． It is 1 to 100 equivalents, more preferably 1 to 10 equivalents.

For example, when R _A ^1a and R _A ^1b are N-phthaloyl groups (in the case of (c) above), by reacting hydrazine hydrate with a compound represented by the above general formula (II) in alcohol, The phthaloyl group can be eliminated. Examples of the alcohol used include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-
Butyl alcohol and tert-butyl alcohol can be exemplified. The amount of alcohol used is, for example, 1 to 100 times, preferably 3 to 50 times, and more preferably 5 to 10 times the mass of the compound represented by the general formula (II). The amount of hydrazine hydrate used is, for example, 1 to 50 equivalents, preferably 2 to 20 equivalents, and more preferably 3 to 10 equivalents based on the number of moles of the compound represented by the general formula (II). ..

For example, in the case where R _A ^1a and/or R _A ^1b is a benzyl group or an allyl group (case (d) above), the above general formula (
The compound represented by II) can be deprotected. The amount of the liquid ammonium used is, for example, 1 to 100 times, preferably 3 to 50 times, and more preferably 5 to 10 times the amount of the compound represented by the general formula (II). Is. The amount of metallic sodium used is, for example, from 2 to 50 based on the number of moles of the compound represented by the general formula (II).
It is equivalent, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. The deprotection can be performed by appropriately selecting the conditions in which the heavy metal catalyst is not used as in the above example, and the conditions are not limited.

The deprotection in step c) is preferably performed without using a heavy metal catalyst as described above, but can be performed using a heavy metal catalyst. For example, when the polyalkylene glycol derivative obtained by the production method of the present invention is used for an application (for example, cosmetics, hair growth agents, surfactants, etc.) in which the incorporation of heavy metals is not an essential problem, step c) It is also conceivable to use such heavy metal catalysts in. When step c) is carried out using a heavy metal catalyst, a general heavy metal catalyst as described above may be used in a conventional manner, and the method is not particularly limited.

When deprotected with an acid catalyst, the formed amine and acid represented by the general formula (III) may form a salt, and the acid may not be removed. At that time, when the generated basic compound is added and reacted with an acid, a salt of the added basic compound and an acid is formed, and the amine represented by the general formula (III) can be taken out. The salt formed at this time can be removed by filtration. If the resulting salt is incorporated into the polymer, the salt can be removed using an adsorbent. As the adsorbent at that time, the adsorbent as described in the above step b) can be used, but it is not particularly limited. The amount of the adsorbent used is 0.01 to 10 times, preferably 0.1 to 8 times, and more preferably 0.3 to 6 times the mass of the compound represented by the general formula (III). There is no particular limitation. Examples of the basic compound used include, but are not limited to, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, potassium methoxide and the like. The addition amount of the basic compound is, for example, 1 to 10 equivalents, preferably 1 to 5 equivalents, and more preferably 1 to 2 equivalents based on the number of moles of the acid catalyst used for deprotection. As a solvent for filtration, the reaction solvent may be used as it is, or may be replaced with a solvent in which a salt is easily precipitated and then filtered. Specific examples of the solvent in which a salt is easily precipitated include THF, ethers such as 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, ethyl acetate, n-butyl acetate, γ-butyrolactone and the like. Examples include, but are not limited to, esters, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile, and the like. Aromatic hydrocarbons such as benzene, toluene, and xylene are preferable in order to enhance the filterability. These solvents may be used alone or in combination of one kind or two or more kinds. In that case, the mixing ratio is not particularly limited.

When removing the acid catalyst, it is possible to add the adsorbent directly to the reaction system without adding the basic compound, but in that case the filterability may decrease, so after adding the above-mentioned basic compound It is preferred to use adsorbents.

After the deprotection, for example, the compound represented by the general formula (III) may be crystallized as it is in a poor solvent, or may be crystallized after substituting it with a good solvent. Crystallization may be performed after the reaction with the compound and the treatment with the adsorbent. Specific examples of the good solvent in that case include ethers such as THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, n-butyl acetate and γ-butyrolactone. Kind,
Examples thereof include, but are not limited to, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile, and the like. These solvents can be used alone,
It is also possible to use one kind or a mixture of two or more kinds. In that case, the mixing ratio is not particularly limited. The concentration after solvent replacement is, for example, 5 to 50% by mass, preferably 10 to 40% by mass,
More preferably, it is 10 to 30 mass %.

Examples of the poor solvent used for crystallization of the compound represented by the general formula (III) include compounds represented by the general formula (II
A compound having a low solubility of the compound represented by I) is used. Specific examples of the poor solvent include hydrocarbons such as hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane and cyclooctane, and ethers such as diethyl ether, diisopropyl ether and di-n-butyl ether. Used for. The amount of the poor solvent used is not particularly limited, but is, for example, 5 to 100 relative to the mass of the compound represented by the general formula (III).
The amount of solvent used is preferably 5 to 50 times, more preferably 5 to 20 times. The poor solvent may be used alone or in combination of one kind or two or more kinds. It is also possible to use it as a mixture with another solvent. Other solvents that can be mixed include ethyl acetate, n-butyl acetate, esters such as γ-butyrolactone, acetone,
Ketones such as methyl ethyl ketone and methyl isobutyl ketone, hydrocarbons such as benzene, toluene, xylene and cumene, ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane, methanol, ethanol, isopropyl alcohol, ethylene glycol monomethyl ether and the like. Alcohols, dimethylsulfoxide (DMSO), N,
Examples thereof include N-dimethylformamide (DMF) and acetonitrile, but are not limited thereto. When two or more solvents are mixed and used as the poor solvent, the mixing ratio is not particularly limited.

In step c), after the solid of the compound represented by the general formula (III) is precipitated by crystallization, the solid may be washed and purified if necessary. The solvent used for washing is preferably the same poor solvent as described above, but is not particularly limited including the amount of the washing solvent used. The compound represented by the general formula (III) can be taken out as a solid by drying the obtained solid under reduced pressure.

In addition, in the present embodiment, the amino group of the compound represented by the general formula (III) is obtained by deprotection in the above step c), and therefore, a by-product which can be produced by the method described in Patent Document 5, for example. (Compounds represented by the following (IV) to (VI)) are not substantially formed, and finally a narrowly dispersed and highly pure polyalkylene glycol having an amino group at the terminal represented by the general formula (III). Derivatives can be synthesized. On the other hand, for example, when hydrogenating a cyanoethylated product by a method described in Patent Document 5 to obtain a polyalkylene glycol derivative having an amino group, β-elimination of acrylonitrile accompanies the PEG represented by the following general formula (VI). It cannot prevent the formation of derivatives. In the hydrogen reduction step, a secondary amine represented by the following general formulas (IV) and (V) is obtained by adding an amine as a product to imine which is a reduction intermediate of nitrile.
A tertiary amine compound may be produced as a by-product. Although these side reactions can be suppressed by adding ammonia or acetic acid to the reaction system, it is difficult to completely control them by a conventional method.

（上記一般式（ＩＶ）〜（ＶＩ）中、Ｒ_Ａ ^２、Ｒ_Ａ ^３、Ｒ_Ａ ^４、Ｒ_Ａ ^５、及びｎは上記一
般式（ＩＩＩ）中のＲ_Ａ ^２、Ｒ_Ａ ^３、Ｒ_Ａ ^４、Ｒ_Ａ ^５、及びｎと同一である。）

(In the general formulas (IV) to (VI), R _A ² , R _A ³ , R _A ⁴ , R _A ⁵ , and n are R _A ² , R _A ³ , and R _{A in the} general formula (III). ⁴ , which is the same as R _A ⁵ , and n.)

[Post-treatment process]
After step c), optionally a post-treatment step can be carried out in which the compound of general formula (III) is purified using a strongly acidic cation exchange resin. Further, when the protecting group in the compound represented by the general formula (II) obtained in step b) is a protecting group which can be deprotected with an acid, after the step b), the strong acidic cation exchange resin is used. By performing the post-treatment process, deprotection can be performed at the same time, and the process can be simplified. That is, in this case, step c) (the step of obtaining the compound represented by the general formula (III) by deprotecting the compound represented by the general formula (II)) is specifically the operation of the following post-treatment step. Can be carried out.

In the post-treatment step, a reaction product (crude product) containing the compound represented by the general formula (III) obtained in step c) or the compound represented by the general formula (II) obtained in step b) The reaction product (crude product) containing is reacted with a strongly acidic cation exchange resin. As the method for reacting the crude product obtained in step c) or step b) with the strongly acidic cation exchange resin, a method in which the crude product solution is flowed through a column packed with an ion exchange resin to adsorb the crude product solution or a resin is used. Examples include a method of circulating the crude product solution between the cartridge filled with and the reaction tank in which step c) or step b) is performed, but the reaction method is not particularly limited. When a post-treatment step is carried out after the step b), the compound represented by the general formula (II) and water or a monohydric alcohol solvent having 1 to 5 carbon atoms are used under the catalyst of a strongly acidic cation exchange resin. After deprotection by reacting
The compound represented by (III) can be adsorbed on a strongly acidic cation exchange resin.

Specific examples of the strong acid cation exchange resin include Amberlite series (Organo Co., Ltd.)
IR120B, IR124B, 200CT, 252), Organo's Amberjet series (1020, 1024, 1060, 1220), Mitsubishi Chemical's Diaion series (for example, SK104, SK1B, SK110, SK112, PK208, PK2).
12, PK216, PK218, PK220, PK228, UBK08, UBK10, U
BK12, UBK510L, UBK530, UBK550), DO manufactured by Dow Chemical Co., Ltd.
WEX series (50W x 2 50-100, 50W x 2 100-200, 50W x 4
100-200, 50W x 8 50-100, 50W x 8 100-200, 50W x 8
200-400, HCR-S, HCR-W2(H), etc. are preferably used, but not limited thereto. The amount of the strongly acidic cation exchange resin used is, for example, 1 to 50 times, preferably 1 to 30 times, and more preferably 1 to 20 times the mass of the compound represented by the general formula (III). is there.

When a strong acid cation exchange resin is used, it may be used after treating the strong acid cation exchange resin with an acidic compound in advance. Strongly acidic cation exchange resins are often sold in the state of alkali metal salts of sulfonic acid, and by treating them with an acidic compound in advance, the sulfo group can be regenerated and the reaction efficiency can be increased. This is because. In this case, examples of the acidic compound used include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid,
It is not limited to these. The amount of these acidic compounds used is, for example, 1 to 15 times, preferably 1 to 10 times, and more preferably 1 to 8 times the mass of the strongly acidic cation exchange resin. After treating the strongly acidic cation exchange resin with the acidic compound, the acidic compound is separated from the resin by washing with water, and if necessary, water is separated with a water-soluble organic solvent such as methanol or ethanol.

In this post-treatment step, impurities other than the compound represented by the general formula (III) (the above general formula (
Compounds or salts represented by VIII) can also be separated. That is, the crude product after step c) or step b) is reacted with a strongly acidic cation exchange resin to adsorb the compound represented by the general formula (III) onto the strongly acidic cation exchange resin, and then water is added. Alternatively, a substance other than the target compound represented by the general formula (III) can be separated by washing the strongly acidic cation exchange resin with a monohydric alcohol having 1 to 5 carbon atoms. Examples of the monohydric alcohol having 1 to 5 carbon atoms used in this washing include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol. , Isopentyl alcohol, neopentyl alcohol, and the like, but are not limited thereto. When cleaning, water or a monohydric alcohol may be used alone, or a mixture of water and one or more alcohols, or a mixture of two or more alcohols may be used. In that case, the mixing ratio is not particularly limited.
The amount of water or monohydric alcohol having 1 to 5 carbon atoms to be used is not particularly limited, but is, for example, 1 to 30 times, preferably 1 to 20 times the amount of the strongly acidic cation exchange resin used. , And more preferably 1 to 10 times.

By reacting the strongly acidic cation exchange resin having the compound represented by the general formula (III) adsorbed with the basic compound in water or a monohydric alcohol having 1 to 5 carbon atoms, the compound represented by the general formula (III)
) Is extracted into water or a monohydric alcohol. When carrying out the reaction, water or a monohydric alcohol may be used alone, or a mixture of water and one or more alcohols, or a mixture of two or more alcohols may be used. In that case, the mixing ratio is not particularly limited. The strongly acidic cation exchange resin may be reacted with the basic compound by flowing a solution of the basic compound into a packed column to carry out the reaction, or by using a resin-filled cartridge and a reaction tank in which the step c) is performed. Examples thereof include a method of circulating a solution of a basic compound between them, but the reaction method is not particularly limited.

As the monohydric alcohol used in the extraction, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, isopentyl alcohol, neopentyl alcohol. Can be exemplified. The amount of water or monohydric alcohol used is not particularly limited, but is, for example, 1 to 30 times, preferably 1 to 20 times, and more preferably 1 to 10 times the mass of the strongly acidic cation exchange resin used. Is the amount.

As the basic compound used in the extraction, ammonia dissolved in water or an organic solvent (for example, ammonia water or a methanol solution of ammonia) is preferably used.
Secondary and tertiary aliphatic amines, mixed amines, aromatic amines, heterocyclic amines and the like can also be used. Examples of primary aliphatic amines include methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, s.
Examples of secondary aliphatic amines such as ec-butylamine, tert-butylamine and ethylenediamine include dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, di-sec-. Examples of tertiary aliphatic amines such as butylamine include trimethylamine, triethylamine and tri-n.
-Propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, tri-sec-butylamine, and the like, as mixed amines, for example, dimethylethylamine, methylethylpropylamine, benzylamine, phenethylamine, benzyldimethylamine, and the like. Specific examples of aromatic amines and heterocyclic amines include aniline derivatives (for example, aniline, N-methylaniline, N-ethylaniline, N-propylaniline,
N,N-dimethylaniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, ethylaniline, propylaniline, trimethylaniline, 2-nitroaniline,
3-nitroaniline, 4-nitroaniline, 2,4-dinitroaniline, 2,6-dinitroaniline, 3,5-dinitroaniline, N,N-dimethyltoluidine, etc.), diphenyl(p-tolyl)amine, methyldiphenylamine , Triphenylamine, phenylenediamine, naphthylamine, diaminonaphthalene and pyridine derivatives (for example, pyridine, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, 4-(1-butylpentyl)pyridine, dimethylpyridine, trimethylpyridine, triethylpyridine, Phenylpyridine, 3-methyl-2-phenylpyridine, 4-tert-butylpyridine, diphenylpyridine, benzylpyridine, methoxypyridine, butoxypyridine, dimethoxypyridine, 4-pyrrolidinopyridine, 2-(1-ethylpropyl)pyridine, Aminopyridine, dimethylaminopyridine, etc.) can be exemplified, but not limited thereto. Also,
An alkaline aqueous solution such as potassium hydroxide or sodium hydroxide may be used as the basic compound. The amount of the basic compound used is, for example, 0.1 to 100 times, preferably 0.1 to 10 times, and more preferably 0.1 to 100 times the mass of the strongly acidic cation exchange resin used.
5 times the amount.

Thus, by performing steps a) to c), or optionally, steps a) to c
By further carrying out the pre-process 1, 2 and/or the post-treatment process before and/or after the step (1), the compound represented by the general formula (III) (a narrow-dispersion and high-purity polyamine having an amino group at the terminal) (Alkylene glycol derivative) can be produced.

That is, according to another aspect of the present invention, a compound represented by the general formula (II
The present invention relates to a narrowly dispersed and highly pure polyalkylene glycol derivative having an amino group at the terminal, which is represented by I).

A general result obtained after steps a) to c), or optionally by further carrying out pre-steps 1, 2 and/or post-treatment steps before and/or after steps a)-c). In the compound represented by the formula (III), the initiation reaction is sufficiently faster than the growth reaction during the polymerization, the water content which is a factor of the termination reaction is less mixed into the reaction system, and the polymerization initiator is added to the polymerization solvent. Since it is uniformly dissolved, it can be obtained as a narrowly dispersed polymer. That is, the compound represented by the general formula (III) produced by the production method of the present embodiment has narrow dispersibility and its degree of dispersion (
The weight average molecular weight (Mw)/number average molecular weight (Mn) is, for example, 1.0 to 1.20,
It is preferably 1.0 to 1.10, and more preferably 1.0 to 1.06. Also,
The molecular weight of the compound represented by the general formula (III) produced by the production method of the present embodiment is preferably 5,000 to 25,000 as the weight average molecular weight (Mw), and 8,000.
˜15,000 is more preferable. In the present specification, the molecular weight and dispersity of a polymer refer to values measured by gel permeation chromatography (hereinafter abbreviated as GPC).

A product obtained after steps a) to c), or optionally obtained by further carrying out pre-steps 1, 2 and/or post-treatment steps before and/or after steps a)-c). General formula in things
The amount of the compound represented by (IV) and the compound represented by the general formula (V) mixed is expressed by the general formulas (III), (IV), and (V) in terms of area content (%). The area of the compounds represented by the general formulas (IV) and (V) is preferably 3% or less, more preferably 2% or less, based on the total area of the compound. Most preferably, the obtained product does not contain the compound represented by the general formula (IV) or the compound represented by the general formula (V). In fact, according to this embodiment, neither the compound represented by the general formula (IV) nor the compound represented by the general formula (V) is produced. The secondary amine represented by the general formula (IV), and the general formula (V)
The tertiary amine represented by has a molecular weight that is twice or three times that of the polyalkylene glycol derivative represented by the general formula (III), which is the main product. Therefore, the production amount can be confirmed by GPC. it can.

A product obtained after steps a) to c), or optionally obtained by further carrying out pre-steps 1, 2 and/or post-treatment steps before and/or after steps a)-c). The amount of the compound represented by the general formula (VI) mixed in the product is 2 mol with respect to the total amount of the compound represented by the general formula (III) and the compound represented by the general formula (VI). % Or less, more preferably 1 mol% or less. Most preferably, the resulting product has the general formula (
It does not include the compound represented by VI). In addition, in reality, according to the present embodiment,
The compound represented by the general formula (VI) is not formed. The compound represented by the general formula (VI) is
Since it has an alcohol as a functional group, it is determined by proton nuclear magnetic resonance (1H-NMR) as compared to the amine α-methylene of the polyalkylene glycol derivative represented by the general formula (III), which is the main product, in the composition ratio content. The rate (mol%) can be determined.

It may also be obtained after steps a) to c), or optionally by further carrying out pre-steps 1, 2 and/or post-treatment steps before and/or after steps a) to c). The obtained product is substantially free of by-products (compounds represented by the general formulas (IV) to (VI)) that can be produced by the conventional method as described above. Specifically, the above-mentioned GPC and 1H-NMR
The total amount of the compounds represented by the general formula (III), which is the main product, converted from the measurement results according to the formula (A) is represented by X _A , the general formula (IV), the general formula (V), and the general formula (VI). When the total amount of by-products including compounds is X _B , X _A /(X _A +X _B ) is preferably 0.95 or more,
More preferably, it is 0.97 or more. Most preferably, the resulting product is free of by-products as described above. In addition, actually, according to the present embodiment, these by-products are not generated.

It may also be obtained after steps a) to c), or optionally by further carrying out pre-steps 1, 2 and/or post-treatment steps before and/or after steps a)-c). In the product
The heavy metal impurity content measured by a high frequency inductively coupled plasma mass spectrometer (ICP-MS) is preferably 100 ppb or less, more preferably 10 ppb or less. The measurement of the amount of heavy metal impurities in the product is generally performed using the ICP-MS described above,
The measuring method is not limited. When performing analysis by ICP-MS, the polymer sample is diluted with a solvent and then measured. It is essential that the solvent used is one in which the polymer is dissolved and does not contain a metal. Ultrapure water and N-methyl-2-pyrrolidone for electronics industry are particularly preferable, but not limited thereto. The dilution ratio is not particularly limited, but preferably 10 to 1
It is 0,000 times, more preferably 50 to 1,000 times.

As described above, for example, in the conventional synthesis methods described in Patent Document 4 and Patent Document 5, since the cyano group is converted to an aminomethyl group using a Raney nickel catalyst, for example, when using a polyalkylene glycol derivative for pharmaceutical use In such cases, there is a concern that heavy metal may be mixed in the product. "ICH Q3D: Reported at the Japan-US EU International Conference on Harmonization of Pharmaceutical Regulations (ICH)"
According to the “Guideline for Metal Impurities for Pharmaceuticals”, metal impurities that require risk assessment are As, Pb, Cd, Hg in Class 1, V, Mo in Class 2A,
Se, Co, Class 2B includes Ag, Au, Tl, Pd, Pt, Ir, Os, Rh, Ru, and Class 3 includes Sb, Ba, Li, Cr, Cu, Sn, and Ni. Heavy metals used in the hydrogen reduction reaction include Co, Ni, Pd, Pt, Rh, Ru, Cu, Cr, etc., but these are listed as heavy metals that require risk assessment and will be further reduced in the future. Is required. On the other hand, the method of the present embodiment does not require the use of the heavy metal catalyst as described above, and therefore the heavy metal is not mixed in the product. As a result, it can be said that the production method is suitable for obtaining the compound represented by the general formula (III), which is used particularly for pharmaceutical applications.

[Embodiment 2]
The present invention is represented by a compound represented by the following general formula (1) in which an amino group is protected by a silyl group, and/or a general formula (2) below, as the polymerization initiator, among the above-described Embodiment 1. It is preferable to use a compound (hereinafter sometimes abbreviated as “compound represented by the general formula (1) and/or (2). The same applies to other compounds). The compound represented by the general formula (1) and/or (2) has a high solubility in a polymerization solvent and a high stability as a polymerization initiator, and further can be easily deprotected by an acid catalyst after the polymerization. There are advantages. An embodiment in which the compound represented by the general formula (1) and/or (2) is used as the polymerization initiator will be described below.
Embodiment 2" may be called. Since the second embodiment is a preferable mode of the first embodiment, the description of the overlapping portions will be omitted below.
In addition, the compound represented by the following general formula (1) is the compound represented by the general formula (I) in the above-mentioned Embodiment 1, wherein R _A ^1a and R _A ^1b are each represented by Si(R ¹ ) _3. Is a structure having R _A ² is R ² and R _A ³ is (OR ⁵ ) _m .
In addition, the compound represented by the following general formula (2) is the compound represented by the general formula (I) in the above-mentioned Embodiment 1, wherein R _A ^1a and R _A ^1b are each represented by Si(R ¹ ) _3. Which is a structure having R _A ² is R ³ and R _A ³ is a single bond.

In the second embodiment, the method for producing a polyalkylene glycol derivative in the case of using the compound represented by the general formula (1) and/or (2) as a polymerization initiator is described in steps a′) to c′.
) As below. As shown below, when the compound represented by the general formula (1) is used as the polymerization initiator, the obtained polyalkylene glycol derivative becomes the compound represented by the general formula (3), and the compound represented by the general formula ( When the compound represented by 2) is used, the obtained polyalkylene glycol derivative is the compound represented by the general formula (4).

Step a′) Represented by the following general formula (12) and/or (13) by reacting the polymerization initiator represented by the general formula (1) and/or (2) with an alkylene oxide in a polymerization solvent. Obtaining a compound,
Step b′) A compound represented by the general formula (12) and/or (13) is reacted with a compound represented by the following general formula (5) to give a compound represented by the following general formula (14) and/or (15). A step of obtaining a compound represented by the formula, and step c′) deprotecting the compound represented by the formula (14) and/or (15),
A step of obtaining the compound represented by 3) and/or (4).

In the general formulas (1) to (2) and (12) to (15), each R ¹ independently represents a straight chain having 1 to 6 carbon atoms, or a branched or cyclic group having 3 to 6 carbon atoms. It is a monovalent hydrocarbon group.
Alternatively, R ¹ may be bonded to each other to form a 3- to 6-membered ring with the silicon atom to which they are bonded. Specific examples of R ¹ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group. Group, cyclopentyl group, cyclohexyl group and the like. In addition, when R ¹ 's are bonded to each other to form a ring with a silicon atom, groups in which one hydrogen atom is eliminated from these groups and the like can be mentioned. (Note that, as described above, R ¹ in the second embodiment is a separate code having a different definition from R _A ^1a and/or R _A ^{1b in the} first embodiment, and “(1) described in the first embodiment is described. A) the same as R ^{1 in} “protecting group having a structure represented by Si(R ¹ ) ₃ ”. Note that it is easy to introduce two protecting groups on nitrogen, and a general formula ( From the viewpoint of easy synthesis of the compound represented by 6) and/or (7), R ¹ is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

In the above general formulas (1), (3), (12), and (14), R ² is a straight chain having 1 to 6 carbon atoms, or a branched or cyclic divalent group having 3 to 6 carbon atoms. It is a hydrocarbon group. Specific examples of R ² include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group. Examples thereof include a group in which one hydrogen atom is eliminated from each of the group, cyclopentyl group, and cyclohexyl group. Incidentally, R ² in the present embodiment 2 corresponds to R _A ² in the above embodiment 1, its definition is the same as the definition of R _A ² in the first embodiment.

In the general formulas (2), (4), (13), and (15), R ³ is a linear divalent hydrocarbon group having 4 to 6 carbon atoms. Specific examples of R ³ include an n-butyl group, an n-pentyl group,
Examples thereof include a group in which one hydrogen atom has been removed from each of the n-hexyl groups. Note that, as described above, R ³ in the second embodiment is a different code having a different definition from R _A ^{3 in the} first embodiment.

In the above general formulas (3) to (5) and (14) to (15), R ⁴ is a hydrogen atom or an optionally substituted linear, branched or cyclic carbon atom having 1 to 12 carbon atoms. It is a hydrogen group, and the hydrocarbon group may contain a hetero atom. Specific examples of R ⁴ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, octyl group, Decyl group, dodecyl group, phenyl group, 0-tolyl group, m-tolyl group, p-tolyl group, 2,3-
Xylyl group, 2,4-xylyl group, 2,5-xylyl group, 2,6-xylyl group, 3,4-
Examples thereof include xylyl group, 3,5-xylyl group, mesityl group, vinyl group, and allyl group. Examples of R ⁴ of the substituted structure include, for example, acetalized formyl group, cyano group, formyl group,
A carboxyl group, an amino group, an alkoxycarbonyl group having 1 to 6 carbon atoms, an acylamide group having 2 to 7 carbon atoms, the same or different tri(alkyl having 1 to 6 carbon) siloxy group, siloxy group, silylamino group, maleimide group, Examples thereof include a thiol group, a hydroxyl group, a methacryloyloxy group, an acryloyloxy group, an active ester group and an azido group. Specific examples of R _A ⁴ having a substituent include those represented by the following structural formulas, but the present invention is not limited thereto. In addition, the following formula shows the terminal part of R ⁴ of the substituted structure, and the dotted line in the formula shows that the hydrocarbon part of R ⁴ can take the variations as exemplified above. Such a substituent may be further protected with any appropriate protecting group.

In addition, R ⁴ in the second embodiment corresponds to R _A ⁴ in the first embodiment,
The definition is the same as the definition of R _A ^{4 in} the first embodiment.

In the general formulas (1), (3) to (5) and (12) to (15), R ⁵ has 2 to 8 carbon atoms.
Is an alkylene group. Especially, it is preferable that it is a C2-C3 alkylene group. That is, R ⁵ is preferably an ethylene group or a propylene group. The (OR ⁵ ) unit may be composed of only one kind of oxyalkylene group, for example, an oxyethylene group or an oxypropylene group, or may be a mixture of two or more kinds of oxyalkylene groups. Two
When one or more kinds of oxyalkylene groups are mixed, (OR ⁵ ) may be a random polymerization of two or more different oxyalkylene groups or a block polymerization. Incidentally, R ⁵ in the present embodiment 2 corresponds to R _A ⁵ in the above embodiment 1, its definition is the same as the definition of R _A ⁵ in the first embodiment.

In the above general formulas (1) to (2) and (12) to (13), M represents an alkali metal, and M
The specific example of is as described in the first embodiment.

In the general formulas (1), (3), (12) and (14), m represents an integer of 1 to 3. Considering the boiling point of the compound at the time of distillation, m is preferably an integer of 1-2.

In the general formulas (1) to (4) and (12) to (15), r, k, n, and L are
It is the same as r, k, n, and L described in the first embodiment.

In the selection of each compound used in each step of the production method of Embodiment 2, the compound represented by the general formula (3) and/or (4) can be obtained so as to obtain the compound of the general formula (3) and/or (4) as a desired final product. 1), (2), (5), and (12) to (15), desired R ¹ , R ² , and R ³
, R ⁴ , R ⁵ , m, r, k, n, and L can be selected.

In the second embodiment, prior to the steps a′) to c′), as an optional step,
[Pre-process 1′] and [pre-process 2′] can be performed. [Pre-Step 1′] and [Pre-Step 2′] are steps for producing a compound represented by the following general formula (6) and/or (7) which is a raw material (starting material) of a polymerization initiator ([Previous Step Step 1′]), and a step ([previous step 2′]) of producing a compound represented by the general formula (1) and/or (2) which is a polymerization initiator. As the pre-process, the [pre-process 2′] may be performed after the [pre-process 1′], or only the [pre-process 2′] may be performed without the [pre-process 1′]. ..

Further, in the second embodiment, after the steps a′) to c′), as an optional step, the obtained target compound (a compound represented by the general formula (3) and/or (4)) is obtained. You may perform the post-treatment process which refine|purifies.

In the following description of the second preferred embodiment, [pre-process 1′] and [pre-process 1′] will be performed in chronological order.
The pre-process 2′], the process a′) to the process c′), and the post-treatment process will be described in this order. It should be noted that description of portions having the same contents as those in the above-described first embodiment will be appropriately omitted.

[Previous process 1']
The [previous step 1′] includes the following general formula (6) and/or (which is used as a precursor of the polymerization initiator.
This is a step of synthesizing the compound represented by 7).

（上記一般式（６）及び（７）中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍは、上記一般式（１
）及び（２）について定義したとおりであって、上記一般式（１）及び（２）中のＲ^１、
Ｒ^２、Ｒ^３、Ｒ^５、及びｍと同一である。）

(In the general formulas (6) and (7), R ¹ , R ² , R ³ , R ⁵ , and m are the same as those in the general formula (1).
) And (2) as defined above, wherein R ¹ in the general formulas (1) and (2) above,
Identical to R ² , R ³ , R ⁵ , and m. )

[Previous step 1′] includes, for example, the following steps (1-1) to (1-2) and the following steps (2-1) to (2)
-2), but is not limited to this.

（上記一般式（６ａ）、（６ｂ）、（７ａ）、（８）、及び（９）中、Ｒ^１、Ｒ^２、Ｒ^３
、Ｒ^５、及びｍは、一般式（１）及び（２）について定義したとおりであって、一般式（
１）及び（２）中のＲ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍと同一である。Ｌ^１は脱離基を表し
、その具体例は上記実施形態１に記載したとおりである。Ｒ^６は炭素数１〜５の炭化水素
基である。）

(In the above general formulas (6a), (6b), (7a), (8), and (9), R ¹ , R ² , and R ³
, R ⁵ and m are as defined for general formulas (1) and (2),
It is the same as R ¹ , R ² , R ³ , R ⁵ and m in 1) and (2). L ¹ represents a leaving group, and specific examples thereof are as described in the above Embodiment 1. R ⁶ is a hydrocarbon group having 1 to 5 carbon atoms. )

Specific examples of R ⁶ include methyl group, ethyl group, n-propyl group, isopropyl group, n-
Examples thereof include, but are not limited to, a butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, a cyclopropyl group, a cyclobutyl group and a cyclopentyl group.

Since the silicon-nitrogen bond is generally weaker than the silicon-oxygen bond, in the deprotection reaction represented by the above formula (1-2) or formula (2-2), the silicon-nitrogen bond originally has priority. Be disconnected. However, in the case of this reaction in Embodiment 2, since two bulky protecting groups (trialkylsilyl groups) are present on the nitrogen, the silicon-oxygen bond can be preferentially cut off due to the steric hindrance. Thus, after protecting the amino group with two bulky protecting groups, and also protecting the hydroxy group with one protecting group of the same structure (ie, applying all three protecting groups at the amino and hydroxy groups). Later), by taking advantage of the bulkiness that the amino group has two protecting groups, by deprotecting only the hydroxy group preferentially, alcohols in which only the amino group was silylated, which was difficult in the conventional method. Can be synthesized.

The above steps (1-1) and/or (2-1) can be performed, for example, as follows. Even if a basic compound is added to the compound represented by the general formula (6a) and/or (7a) without a solvent, and then the compound represented by the general formula (6b) is added dropwise and mixed to cause a reaction. Good, after dissolving the compound represented by the general formula (6a) and/or (7a) in a suitable solvent, the basic compound is added, and then the compound represented by the general formula (6b) is added dropwise, You may make it react by mixing. The amount of the compound represented by the general formula (6b) used is, for example, 3 to 15 times, preferably 3 to 15 times, the molar number of the compound represented by the general formula (6a) and/or (7a).
The amount is 10 times, more preferably 3 to 5 times.

When a solvent is used in the above step (1-1) and/or (2-1), specific examples of the solvent include ethers such as THF and 1,4-dioxane, aromatic compounds such as benzene, toluene, xylene. Hydrocarbons, halogens such as methylene chloride, N,N-dimethylformamide and N-
Examples thereof include, but are not limited to, methyl-2-pyrrolidone, acetonitrile, acetone and the like. The amount of the solvent used is not particularly limited, but is, for example, 1 to 20 times, preferably 2 to 10 times, and more preferably the mass of the compound represented by the general formula (6a) and/or (7a). Is an amount of 2 to 5 times.

Specific examples of the basic compound used in the above step (1-1) and/or (2-1) include:
Hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. , Metal hydrides such as sodium hydride and potassium hydride, primary, secondary and tertiary aliphatic amines, mixed amines, aromatic amines, heterocyclic amines, aqueous ammonia, etc. It can be used, but is not limited to. The amount of the basic compound used is determined by the formula (6)
The amount is, for example, 3 to 15 times, preferably 3 to 10 times, and more preferably 3 to 5 times the mol number of the compound represented by a) and/or (7a).

The reaction temperature in the above step (1-1) and/or (2-1) can be carried out within the range from the melting point to the boiling point of the solvent used, and for example, -60°C to 150°C, preferably 0°C to 8
It is 0°C. The reaction is terminated by gas chromatography according to the general formula (6a) and/or (7).
It can be the time when the compound represented by a) disappears or the compound represented by the general formula (8) and/or (9) is obtained as a main product.

Moreover, the said process (1-2) and/or (2-2), for example, general formula (8) and/or (
It can be carried out by treating the compound represented by 9) with a base. In particular,
For example, it can be implemented as follows. Once the compound represented by the general formula (8) and/or (9) is purified and taken out, the compound represented by the general formula (8) and/or (9) is dissolved in R ⁶ OH to prepare a catalyst. Selective deprotection is carried out by adding an amount of R ⁶ ONa. Generate (
Evaporation of R ¹ ) ₃ SiOR ⁶ together with R ⁶ OH under reduced pressure biases the equilibrium from general formulas (8) and/or (9) to general formulas (6) and/or (7). The reaction can be completed by adding R ⁶ OH again for further reaction and repeating the above-mentioned operation of distilling under reduced pressure. R ⁶
The amount of OH used is not particularly limited, but is, for example, 1 to 20 times, preferably 2 to 15 times, and more preferably the mass of the compound represented by the general formula (8) and/or (9). Is 3~
10 times the amount. The amount of R ⁶ ONa used is not particularly limited, but is, for example, 0.01 to 1 times the amount of the compound represented by the general formula (8) and/or (9), and preferably 0.0.
The amount is 1 to 0.5 times, and more preferably 0.01 to 0.1 times.

The reaction temperature in the above step (1-2) and/or (2-2) is, for example, 0°C to 100°C.
, Preferably 30°C to 80°C. The reaction can be terminated when the compound represented by the general formula (8) and/or (9) disappears by gas chromatography. General formula (
The compounds represented by 6) and/or (7) are preferably purified by distillation to remove water. In that case, the water content of the compound represented by the general formula (6) and/or (7) is, for example, 50.
ppm or less, preferably 10 ppm or less, more preferably 5 ppm or less.

As another method for producing the compound represented by the general formula (6) and/or (7), for example, the following steps (1-3) to (1-4) and the following steps (1-5) to (1) -6), the following step (2-3)
(2-4) and the like, but the method is not limited thereto.

（上記一般式（６ｂ）、（６ｃ）、（６ｄ）、（６ｅ）、（６ｆ）、（７ｂ）、及び（７
ｃ）中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍは、一般式（１）及び（２）について定義した
とおりであって、一般式（１）及び（２）中のＲ^１、Ｒ^２、Ｒ^３、Ｒ^５、及びｍと同一で
ある。Ｌ^１、Ｌ^２はそれぞれ脱離基を表し、その具体例は上記実施形態１に記載したとお
りである。ＴｓＣｌは塩化ｐ−トルエンスルホニルの略であり、ＭｓＣｌは塩化メタンス
ルホニルの略である。）

(The above general formulas (6b), (6c), (6d), (6e), (6f), (7b), and (7
In c), R ¹ , R ² , R ³ , R ⁵ , and m are as defined for formulas (1) and (2), and R ^{1 in} formulas (1) and (2) are , R ² , R ³ , R ⁵ , and m. L ¹ and L ² each represent a leaving group, and specific examples thereof are as described in Embodiment 1 above. TsCl is an abbreviation for p-toluenesulfonyl chloride, and MsCl is an abbreviation for methanesulfonyl chloride. )

The steps (1-3) and (2-3) can be carried out in the same manner as the step (i-2) described in the first embodiment.
The steps (1-4) and (1-6) can be performed by the same method as the step (i-3) described in the first embodiment. In the case of the reaction represented by the above (1-4) or (1-6), as described in the step (i-3) of the above-mentioned Embodiment 1, by using an excess amount of the diol, one terminal is preferentially used. The alcohol can be etherified.

The above step (1-5) can be performed, for example, as follows. Embodiment 1
Starting from (6e) synthesized in the same manner as in step (i-1) described in 1., a basic compound is added to the compound represented by the general formula (6e) without a solvent, followed by TsCl or MsCl. May be added and reacted by mixing, or the basic compound is added after dissolving the compound represented by the general formula (6e) in a suitable solvent, and then TsCl or MsCl is added,
You may make it react by mixing. The amount of TsCl or MsCl used is represented by the general formula (6e)
The amount is, for example, 1 to 5 times, preferably 1 to 3 times, and more preferably 1 to 2 times the mol number of the compound represented by.

When a solvent is used in the step (1-5), specific examples of the solvent include THF and 1,4-
Examples thereof include ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogens such as methylene chloride, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile and the like, but are not limited thereto. It is not done. The amount of the solvent used is not particularly limited, but is, for example, 1 to 20 times the amount of the compound represented by the general formula (6e),
The amount is preferably 2 to 10 times, more preferably 2 to 5 times.

Specific examples of the basic compound used in the step (1-5) include hydroxides such as sodium hydroxide, potassium hydroxide and tetramethylammonium hydroxide, and carbonates such as sodium carbonate, potassium carbonate and cesium carbonate. Salts, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, metal hydrides such as sodium hydride and potassium hydride, primary, secondary and tertiary aliphatic amines , Mixed amines, aromatic amines, heterocyclic amines, aqueous ammonia, etc. can be used, but are not limited thereto. The amount of the basic compound used is, for example, 3 to 15 times, preferably 3 to 10 times, and more preferably 3 to 5 times the mol number of the compound represented by the general formula (6e).
It is double amount.

The reaction temperature in the above step (1-5) can be carried out within the range of the melting point to the boiling point of the solvent used, and is, for example, -60°C to 150°C, preferably 0°C to 80°C. The reaction can be terminated when the compound represented by the general formula (6e) disappears by gas chromatography.

The above step (2-4) can be performed, for example, as follows. The above process (2-
The compound represented by the general formula (7c) synthesized in 3) may be reacted as a starting material by adding an aqueous solution of sodium hydroxide without a solvent and mixing them. Alternatively, the compound represented by the general formula (7c) may be added to an appropriate solvent.
You may make it react by adding the sodium hydroxide aqueous solution after melt|dissolving the compound represented by. The amount of sodium hydroxide used is, for example, 1 to 5 times, preferably 1 to 3 times, and more preferably 1 to 2 times the mol number of the compound represented by the general formula (7c). is there.

When a solvent is used in the above step (2-4), specific examples of the solvent include H2O, ethers such as THF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, and methylene chloride. Halogens such as N,N-dimethylformamide and N-methyl-2-
Examples include, but are not limited to, pyrrolidone and acetonitrile. The amount of the solvent used is not particularly limited, but is, for example, 1 to 2 with respect to the mass of the compound represented by the general formula (7c).
The amount is 0 times, preferably 2 to 10 times, and more preferably 2 to 5 times.

The reaction temperature in the above step (2-4) can be carried out within the range of the melting point to the boiling point of the solvent used, and is, for example, -60°C to 100°C, preferably -30°C to 20°C. The reaction can be terminated when the compound represented by the general formula (7c) disappears by gas chromatography.

[Previous process 2']
The [previous step 2′] is carried out by reacting the compound represented by the general formula (6) and/or (7) with an alkali metal or an alkali metal compound to give the following general formula (1) and/or (
This is a step of obtaining the compound represented by 2).

The reaction of [pre-process 2′] can be carried out in the same manner as in the pre-process 2 of Embodiment 1 above. That is, the kind and the amount of the alkali metal or the alkali metal compound used, the kind and the amount of the solvent used, the method of adding the compound to the reaction system, the reaction temperature, etc. are the same as those in the previous step 2 of the first embodiment. It can be appropriately selected within the range described. Further, as the solvent used in [Previous step 2′], the same type of solvent as the polymerization solvent used at the time of polymerization can be used.
Whether or not the polymerization initiator is dissolved in the polymerization solvent during the synthesis of the polymerization initiator can be confirmed in advance. The confirmation method is the same as that described in the previous step 2 of the first embodiment.

As described above, when carrying out the polymerization reaction, a reaction system containing a compound (polymerization initiator) represented by the general formula (1) and/or (2) in order to suppress the production of a diol polymer as a by-product. It is preferable to keep the water content therein as low as possible. In this regard, for example, the compound represented by the general formula (6) has a boiling point of 120 when R ¹ =ethyl group, R ² =CH ₂ CH ₂ CH ₂ , and m=1.
C. (10 Pa) and the compound represented by the general formula (7) has R ¹ =ethyl group, R ³ =
In the case of CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ , the boiling point is as high as 110° C. (10 Pa), and since there is a sufficient boiling point difference with water, it is possible to separate water by performing reduced pressure drying. is there. Therefore, in the [previous step 2′], before the addition of the alkali metal or the alkali metal compound, the compound represented by the general formula (6) and/or (7) is sufficiently dried under reduced pressure and then distilled. Is preferably performed. The range of the water content of the compound represented by the general formula (6) and/or (7) is the same as the range of the water content of the compound represented by the general formula (i) described in the previous step 2 of the first embodiment. The same is true.

As described above, in order to improve the polymerization rate, it is preferable to use a polymerization initiator having a small residual amount of the starting material alcohol. Specifically, after the synthesis of the polymerization initiator in [Previous step 2′] is completed, the polymerization initiator represented by the general formula (1) and/or (2) and the general formula (6) and/or (
The substance ratio with the starting material alcohol represented by 7) is represented by the general formula (I) and the polymerization initiator represented by the general formula (I) described in the previous step 2 of the first embodiment. It is preferable that the range is the same as the substance ratio of the starting material alcohol. It is also possible to distill off the starting material alcohol represented by the general formula (6) and/or (7) under reduced pressure after synthesizing the above-mentioned polymerization initiator, and in that case, the general formula (1) And/or (2) the polymerization initiator and the material amount ratio of the starting material alcohol represented by the general formula (6) and/or (7) also in the previous step 2 of the first embodiment. It is preferable that the ratio is the same as the above-mentioned substance ratio of the polymerization initiator represented by the general formula (I) and the starting material alcohol represented by the general formula (i).

[Step a')]
Step a′) is a step of reacting the compound represented by the general formula (1) and/or (2) with an alkylene oxide in a polymerization solvent. Desirably, the compound represented by the general formula (1) and/or (2) is completely dissolved in a polymerization solvent and then reacted with an alkylene oxide.
According to step a′), the compound represented by the following general formula (12) and/or (13) can be obtained. As the polymerization initiator, either the compound represented by the general formula (1) or the compound represented by the general formula (2) may be used alone, or both may be used together. You may.

Here, since a silicon-oxygen bond is generally stronger than a silicon-nitrogen bond, if a 5-membered ring or 6-membered ring structure containing a silicon-oxygen bond can be formed, it is intramolecularly synthesized during the synthesis of a silyl-protected amino group-containing alkoxide. Therefore, the exchange reaction between the silicon-nitrogen bond and the silicon-oxygen bond may proceed. Therefore, for example, even if an attempt is made to use a compound represented by the following formula (0a) as a polymerization initiator, the polymerization proceeds from the amino group side rather than the alkoxide side, and the target polyalkylene glycol derivative is I can't get it. On the other hand, in the polymerization initiator represented by the general formula (1) and/or (2) used in the second embodiment (for example, the following formulas (1a) and (2a)), nitrogen and O ⁻ By extending the chain length of the chain connecting with oxygen constituting M ⁺ to 4 or more, generation of a 5-membered ring or 6-membered ring structure containing a silicon-oxygen bond is suppressed, and stable in an alkoxide state. The structure can be formed. As a result, the polymerization proceeds from the alkoxide side and the target polyalkylene glycol derivative can be obtained.

The silyl-protected amino group-containing alcohol derivative represented by the general formula (1) and/or (2) used as the polymerization initiator has a structure similar to that of the polymerization solvent in the internal structure,
It can be dissolved in the polymerization solvent without the presence of the starting alcohol. In particular, the polymerization initiator represented by the general formula (1) has an alkylene oxide structure in the molecule, so that when the solvent is an ether solvent such as THF, the phase of the polymerization initiator and the polymerization solvent is The solubility is increased, and the polymerization initiator can be dissolved in the polymerization solvent without the presence of the starting alcohol alcohol. Further, in particular, when the polymerization initiator represented by the general formula (2) has a hydrocarbon structure represented by R ³ in the molecule, for example, when the solvent is a hydrocarbon solvent such as toluene, The compatibility between the polymerization initiator and the polymerization solvent is increased, and the polymerization initiator can be dissolved in the polymerization solvent without the presence of the starting material alcohol. As a result, it becomes possible to polymerize in a homogeneous system under mild conditions, and it becomes possible to produce a narrowly dispersed polyalkylene glycol derivative.

The reaction of step a′) can be carried out as described in step a) of Embodiment 1 above. That is, the type and amount of the polymerization solvent used, the method of adding alkylene oxide to the reaction system, the reaction temperature, and the like can be appropriately selected within the range described in step a) of the above embodiment.

Among them, when using the polymerization initiator represented by the general formula (1), since it has an alkylene oxide structure in the molecule, as a polymerization solvent, a cyclic ether compound having 4 to 10 carbon atoms,
Alternatively, a linear or branched ether compound is preferably used. Specific examples of the cyclic ether compound and the linear or branched ether compound are the step a of the above-mentioned Embodiment 1, respectively.
). When the polymerization initiator represented by the general formula (2) is used, since it has a hydrocarbon structure in the molecule, aromatic hydrocarbons are preferably used as the polymerization solvent. The specific example is also as described in step a) of the above embodiment.

[Step b')]
Step b') is a step of reacting the compound represented by the above general formula (12) and/or (13) obtained in step a') with a compound represented by the following general formula (5). .. The compounds represented by the following general formulas (14) and (15) can be obtained by the step b′).
R ⁴ (OR ⁵ ) _k L (5)

The reaction of step b′) can be carried out in the same manner as described in step b) of Embodiment 1 above. That is, the method of adding the compound represented by the general formula (5) to the reaction system, the type and amount of the solvent used, the type and amount of the base catalyst used, the type of alkali adsorbent used, and The amount used, reaction temperature, crystallization of the compound represented by the general formula (14) and/or (15) obtained, washing, purification, etc. are within the range described in step b) of the above-mentioned embodiment, It can be appropriately selected.

[Step c')]
In step c′), the compound represented by the general formula (14) and/or (15) obtained in step b′) is deprotected. This deprotection is preferably performed without the use of heavy metal catalysts. More preferably, the compound represented by the general formula (14) and/or (15) is deprotected under acidic conditions. Specifically, the compound represented by the general formula (14) and/or (15) is
In the presence of an acid catalyst, it is reacted with water or alcohol (R ⁶ OH: in the formula, R ⁶ is a hydrocarbon group having 1 to 5 carbon atoms) to react with the following general formula (3) and/or (4). It can be converted into a compound represented by. The reaction is carried out by reacting the compound represented by the general formula (14) and/or (15) with water or an alcohol in the presence of an acid catalyst, without a solvent, or in a suitable solvent if necessary. It can be carried out. At that time, since the yield can be improved by moving the equilibrium to the product side, (R ¹ ) ₃ SiOH or (R ¹ ) ₃ SiOR is produced.
⁶ is preferably distilled off under heating or under reduced pressure. The amount of water or alcohol used is not particularly limited, but is, for example, 2 to 4 relative to the number of moles of the general formula (14) and/or (15).
000 equivalents, preferably 10 to 3000 equivalents, more preferably 20 to 2000 equivalents.

Specific examples of the acid catalyst used include formic acid, acetic acid, propionic acid, succinic acid, citric acid,
Carboxylic acids such as tartaric acid, fumaric acid, malic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, nitric acid,
Examples thereof include, but are not limited to, inorganic acids such as phosphoric acid and perchloric acid, benzene sulfonic acids, sulfonic acids such as p-toluene sulfonic acid, and solid acids such as Amberlyst series manufactured by Organo Corporation. The amount of these acid catalysts to be used is represented by general formula (14) and/or (15)
), for example, 0.01 to 500 equivalents, preferably 0.1 to 30 moles of the compound represented by
It is 0 equivalent, and more preferably 0.1 to 150 equivalent. These acidic compounds may be used alone or in combination of one kind or two or more kinds. In that case, the mixing ratio is not particularly limited.

Crystallization, washing, purification and the like of the compound represented by the general formula (3) and/or (4) obtained after deprotection are appropriately selected within the range described in step c) of the above-mentioned Embodiment 1. Can be implemented.

The amino group of the compounds represented by the general formulas (3) and/or (4) is obtained by deprotection in step c′), and thus can be produced by the method described in Patent Document 5, for example, a by-product (see below). (
(Compounds represented by A) to (C-2)) are not produced, and finally the compounds represented by the general formula (3) and/or (4)
It is possible to synthesize a narrowly dispersed and highly pure polyalkylene glycol derivative having an amino group at the end, which is represented by (4). On the other hand, for example, when the method described in Patent Document 5 is used, the formation of the PEG derivative represented by the following general formula (A) cannot be prevented as described above. Also,
In the hydrogen reduction step, secondary and tertiary amine compounds represented by the following general formulas (B-1), (B-2), (C-1) and (C-2) may be by-produced. .. As described above, it is difficult to completely control these side reactions by the conventional method.

（上記一般式（Ａ）、（Ｂ−１）、（Ｂ−２）、（Ｃ−１）、（Ｃ−２）中、Ｒ^２、Ｒ^３
、Ｒ^４、Ｒ^５、ｍ、及びｎは、一般式（３）及び（４）について定義したとおりであって
、一般式（３）及び（４）のＲ^２、Ｒ^３、Ｒ^４、ｍ、及びｎと同一である。）

(In the general formulas (A), (B-1), (B-2), (C-1) and (C-2), R ² and R ^{3 are included.}
, R ⁴ , R ⁵ , m, and n are as defined for the general formulas (3) and (4), and are R ² , R ³ , R ⁴ , and m of the general formulas (3) and (4). , And n. )

[Post-treatment process]
After the step c′), a strong acid cation exchange resin is used to produce the compound represented by the general formula (3) and/or (4).
A post-treatment step for purifying the compound represented by can be carried out. The post-treatment process in this case can also be performed by the same operation as described in the post-treatment process of the first embodiment.

Thus, by performing steps a')-c') (or, optionally, step a')
) To c') and/or after further carrying out a pretreatment step 1', 2'and/or a post-treatment step), a compound represented by the general formula (3) and/or (4) ( A narrowly dispersed and highly pure polyalkylene glycol derivative having an amino group at the terminal can be produced.

That is, according to another aspect of the present invention, a compound represented by the general formula (3)
And/or a narrowly dispersed and highly pure polyalkylene glycol derivative having an amino group at the terminal represented by (4).

Prior to and/or after steps a') to c') obtained after steps a') to c') (or optionally, further pre-steps 1', 2'and/or post-treatment steps are carried out. Properties of the compound represented by the general formula (3) and/or (4) obtained by carrying out, ie, dispersity and weight average molecular weight, by-products (PEG derivative, and secondary and tertiary amine) The mixed amount of the above, the content of heavy metal impurities, and the like are the same as those described for the compound represented by the general formula (III) in the first embodiment.

According to another aspect, the present invention is represented by the above general formula (I), which is used as a polymerization initiator for use in the method for producing a polyalkylene glycol derivative having an amino group at a terminal as disclosed above. And a metal salt of a protected amino group-containing alcohol compound. Among them, the metal salt of the novel silyl-protected amino group-containing alcohol compound represented by the general formula (1) or (2) is preferable. The present invention also relates to a novel protected amino group-containing alcohol compound represented by the above general formula (i), which is used as a raw material (starting material) for the above polymerization initiator. Among them, the novel silyl-protected amino group-containing alcohol compound represented by the general formula (6) or (7) is preferable. The definition, production method, and usage method of these compounds have been described in detail in the production method of the polyalkylene glycol derivative in the above-described Embodiments 1 and 2, and thus the description thereof is omitted.

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the description of the molecular weight in Examples, the values of the weight average molecular weight (Mw) and the number average molecular weight (Mn) are measured by gel permeation chromatography (GPC) as polyethylene glycol equivalent values. The GPC was measured under the following conditions.
Column: TSKgel SuperAWM-H, SuperAW-3000
Developing solvent: DMF (0.01 mol/L lithium bromide solution)
Column oven temperature: 60°C
Sample concentration: 0.20wt%
Sample injection volume: 25 μl
Flow rate: 0.3 ml/min

[Synthesis Example 1] Synthesis of compound represented by formula (iA)
[Synthesis Example 1-1] Synthesis of Compound Represented by Formula (iA-1) A 50 ml three-necked flask was charged with 0.75 g of 2-(3-aminopropoxy)-ethanol, 2.35 g of triethylamine and 2.92 g of toluene. Thereafter, 5.98 g of triethylsilyl trifluoromethanesulfonate (hereinafter referred to as TESOTf) was added dropwise under a nitrogen atmosphere. Then, the mixture was stirred at 80°C for 25 hours. The reaction solution was transferred to a separating funnel, the lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 2.71 g (yield 93.3%) of a silyl protected body (iA-1).
Silyl protected form (iA-1)
Colorless liquid Boiling point 190°C/10Pa
¹ H-NMR (500 MHz, CDCL3): δ=0.63 (18H,q), 0.9
6 (27H,t), 1.69 (2H,m), 2.83 (2H,m), 3.40 (2H,t)
), 3.49 (2H,t), 3.76 (2H,t)

式中ＴＥＳはトリエチルシリル基のことである。

In the formula, TES is a triethylsilyl group.

[Synthesis Example 1-2] Synthesis of compound represented by formula (iA) 2.21 g of silyl-protected compound (iA-1) and 2.70 g of methanol in a 10 ml round-bottomed flask.
, 13 mg of sodium methoxide were charged, and the mixture was stirred at 60° C. for 18 hours. Then, triethylmethoxysilane was distilled off under reduced pressure, 2.70 g of methanol was added again, and the mixture was stirred at 60°C. The same operation was repeated. After the reaction was completed, the reaction mixture was quenched with sodium hydrogen carbonate, the solvent was replaced with toluene, and then the salt was removed by filtration. Then, it was distilled under reduced pressure to obtain 1.50 g (yield 90.0%) of a silyl-protected amino group-containing alcohol compound (iA). As a result of measuring the water content after distillation, the water content was 1 ppm or less.
Silyl-protected amino group-containing alcohol (iA)
Colorless liquid Boiling point 118-122°C/10Pa
¹ H-NMR (500 MHz, CDCL3): δ=0.60 (12H, q), 0.9
3 (18H, t), 1.68 (2H, m), 1.96 (1H, bs), 2.82 (2H,
m), 3.40 (2H, t), 3.50 (2H, m), 3.73 (2H, m)

[Synthesis Example 2] Synthesis of formula (iA) by another method [Synthesis Example 2-1] Synthesis of electrophile (iiA) (2-1-1) Synthesis of silyl protected body (iiA-1) In a 300 ml three-necked flask. 6.0 g of 3-amino-1-propanol, 28.74 g of triethylamine, and 18.0 g of toluene were charged, and then TESOTf75.
0 g was added dropwise. Then, the mixture was stirred at 80°C for 25 hours. The reaction solution was transferred to a separating funnel, the lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 31.47 g (yield 93.3) of the silyl-protected compound (iiA-1).
%)Obtained.
Silyl protected form (iiA-1)
Colorless liquid Boiling point 133-138°C/10Pa
¹ H-NMR (500 MHz, CDCL3): δ=0.60 (18 H, q), 0.9
4 (27H,t), 1.62 (2H,m), 2.83 (2H,m), 3.54 (2H,t)
)

(2-1-2) Synthesis of Silyl-Protected Amino Group-Containing Alcohol (iiA-2) In a 200 ml round-bottomed flask, 30.98 g of silyl protected body (iiA-1) and 30
． 98 g and 0.2 g of sodium methoxide were charged, and the mixture was stirred at 60° C. for 18 hours. Then, triethylmethoxysilane was distilled off under reduced pressure, and 30.98 g of methanol was added again to 60°C.
It was stirred at. The same operation was repeated. After the reaction was completed, the reaction mixture was quenched with sodium hydrogen carbonate, the solvent was replaced with toluene, and then the salt was removed by filtration. After that, toluene was distilled off under reduced pressure to obtain 22.66 g (crude yield 96.4%) of the silyl-protected amino group-containing alcohol compound (iiA-2).
Obtained. ¹ H-NMR spectrum confirmed that this crude product had sufficient purity as an intermediate, and thus (iiA-2) was used as it was in the next step.
Silyl-protected amino group-containing alcohol compound (iiA-2)
Colorless liquid
¹ H-NMR (500 MHz, CDCL3): δ=0.60 (12H, q), 0.9
3 (18H,t), 1.67 (2H,m), 2.85 (2H,m), 3.59 (2H,m)
)

(2-1-3) Synthesis of electrophile (iiA) In a 50 ml three-necked flask, 4.7 g of TsCl, 5 g of methylene chloride and 5.
A solution prepared by dissolving 5.0 g of a silyl-protected amino group-containing alcohol compound (iiA-2) in 10.0 g of methylene chloride was added dropwise while cooling with ice. The mixture was returned to room temperature, stirred for 13 hours, quenched with water, and extracted with toluene. After that, the toluene solution is concentrated and the electrophile (ii
7.6 g (crude yield 100%) of A) was obtained. ¹ H-NMR spectrum confirmed that this crude product had sufficient purity as an intermediate, and thus (iiA) was used as it was in the next step.
Electrophile (iiA)
Brown liquid
¹ H-NMR (500 MHz, CDCL3): δ=0.54 (12H, q), 0.8
9 (18H, t), 1.68 (2H, m), 2.45 (3H, s), 2.71 (2H, m)
), 3.98 (2H, t)

[Synthesis example 2-2] Synthesis of electrophile (iiB) A 200 ml three-necked flask was charged with 15.93 g of 3-bromopropylamine hydrobromide, 27.26 g of triethylamine and 47.79 g of toluene, and then under a nitrogen atmosphere. TE
50.00 g of SOTf was added dropwise. Then, the mixture was stirred at 80° C. for 63 hours. The reaction solution was transferred to a separating funnel, the lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 8.00 g of an electrophile (iiB) (yield 3
0.0%) was obtained.
Electrophile (iiB)
Colorless liquid Boiling point 108°C/30Pa
¹ H-NMR (500 MHz, CDCL3): δ=0.61 (12H,q), 0.9
4 (18H,t), 1.92 (2H,m), 2.90 (2H,m), 3.31 (2H,t)
)

[Synthesis Example 2-3] Synthesis of compound represented by formula (iA) using electrophile (iiA) 6.78 g of ethylene glycol and N-methylpyrrolidone 10 in a 100 ml three-necked flask.
g, and potassium tert-butoxide (1.35 g) were added, and the mixture was stirred for 30 minutes, and then the electrophile (ii.
A solution obtained by dissolving 5.0 g of A) in 15 g of N-methylpyrrolidone was added dropwise at room temperature. 60°C
The temperature was raised to 0, the mixture was stirred for 5 hours, and then the reaction was stopped with 0.18 g of sodium hydrogen carbonate.
Subsequently, the solvent was replaced with diphenyl ether, and the precipitated salt was removed by filtration. Then, the residue was distilled under reduced pressure to obtain 3.16 g of a silyl-protected amino group-containing alcohol (iA) (yield: 65.7%).
)Obtained. As a result of measuring the water content after distillation, the water content was 1 ppm or less (the water content was measured by a Karl Fischer moisture meter, the same applies hereinafter).
Silyl-protected amino group-containing alcohol (iA)
Colorless liquid Boiling point: same as the result obtained in the above [Synthesis example 1-2].
¹ H-NMR (500 MHz, CDCL3): Same as the result obtained in the above [Synthesis example 1-2].

式中Ｔｓはパラトルエンスルホニル基、ｔ−ＢｕＯＫはカリウムｔｅｒｔ−ブトキシド
、ＮＭＰはＮ−メチルピロリドンのことである。

In the formula, Ts is a paratoluenesulfonyl group, t-BuOK is potassium tert-butoxide, and NMP is N-methylpyrrolidone.

[Synthesis Example 2-4] Synthesis of compound represented by formula (iA) using electrophile (iiB) 2.98 g of ethylene glycol and N-methylpyrrolidone in a 200 ml three-necked flask.
0 g and 0.54 g of potassium tert-butoxide were charged, and after stirring for 30 minutes, the electrophile (i
A solution of 2.00 g of iB) dissolved in 10.0 g of N-methylpyrrolidone was added dropwise at room temperature. The temperature was raised to 60° C., the mixture was stirred for 5 hours, and then the reaction was stopped with 0.08 g of sodium hydrogen carbonate. Subsequently, the solvent was replaced with diphenyl ether, and the precipitated salt was removed by filtration.
Then, the residue was distilled under reduced pressure to obtain 1.07 g of a silyl-protected amino group-containing alcohol (iA) (yield:
4.0%) was obtained. As a result of measuring the water content after distillation, the water content was 1 ppm or less.
Silyl-protected amino group-containing alcohol (iA)
Colorless liquid Boiling point: same as the result obtained in the above [Synthesis example 1-2].
¹ H-NMR (500 MHz, CDCL3): Same as the result obtained in the above [Synthesis example 1-2].

[Synthesis Example 3] Synthesis of compound represented by Formula (iB) [Synthesis Example 3-1] Synthesis of compound represented by Formula (iB-1) 5.00 g of 6-amino-1-hexanol in a 200 ml three-necked flask. , Triethylamine 15.68 g and toluene 15.00 g were charged, and then TESOTf4 was added in a nitrogen atmosphere.
0.91 g was added dropwise. Then, the mixture was stirred at 80°C for 25 hours. Transfer the reaction solution to a separating funnel,
The lower layer was separated, and the upper layer was distilled under reduced pressure to obtain 18.39 g of the silyl protected body (iB-1) (yield 93
． 0%) was obtained.
Silyl protected form (iB-1)
Colorless liquid Boiling point 180°C/10Pa
¹ H-NMR (500 MHz, CDCL3): δ=0.63 (18H,q), 0.9
6 (27H,t), 1.69 (8H,m), 2.83 (2H,m), 3.40 (2H,t)
)

[Synthesis Example 3-2] Synthesis of Compound Represented by Formula (iB) A silyl protected body (iB-1) (5.00 g) and methanol (5.00 g) were placed in a 50 ml one-necked flask.
, 29 mg of sodium methoxide were charged, and the mixture was stirred at 60° C. for 18 hours. Then, triethylmethoxysilane was distilled off under reduced pressure, and 5.00 g of methanol was added again and the mixture was stirred at 60°C. The same operation was repeated. After the reaction was completed, the reaction mixture was quenched with sodium hydrogen carbonate, the solvent was replaced with toluene, and then the salt was removed by filtration. Then, the residue was distilled under reduced pressure to obtain 3.35 g (yield 89.0%) of a silyl-protected amino group-containing alcohol compound (iB). As a result of measuring the water content after distillation, the water content was 1 ppm or less.
Silyl-protected amino group-containing alcohol (iB)
Colorless liquid Boiling point 108-112°C/10Pa
¹ H-NMR (500 MHz, CDCL3): δ=0.60 (12H, q), 0.9
3 (18H,t), 1.68 (8H,m), 2.82 (2H,m), 3.40 (2H,t)
)

[Synthesis Example 4] Synthesis of compound represented by Formula (IA) [Synthesis Example 4-1] Synthesis of compound represented by Formula (IA) Hydrogenation in a 50 mL three-necked flask in a glove box under a nitrogen atmosphere. Potassium (manufactured by Kanto Kagaku Co., Ltd., mineral oil type) was added, the mineral oil was separated by washing with hexane, and vacuum dried for about 2 hours to obtain 0.50 g (12.5 mmol) of potassium hydride. In the flask, 7.71 g of distilled THF was added with a syringe, and the compound of the formula (iA) 4.4
4 g (12.8 mmol) was added dropwise at room temperature. After stirring at room temperature for 1 hour, stirring was performed at 50° C. for 2 hours, and 12.40 g (1.02 mmol) of a THF solution of the compound represented by the formula (IA).
/G) was obtained. At this time, neither salt precipitation nor cloudiness was observed ((IA) mass/THF solution mass=39.8 wt %). The substance amount ratio of the polymerization initiator (IA) synthesized by the above reaction and the starting material alcohol (iA) is 98:2 (mol %). The reaction scheme is shown below.

[Synthesis Example 4-2] Alternative synthesis of compound represented by Formula (IA) Naphthalene 2.02 in 100 mL three-necked flask in a glove box under nitrogen atmosphere.
g and 0.68 g of potassium were weighed and vacuum dried for 1 hour. Then, the atmosphere was returned to a nitrogen atmosphere, and 19.65 g of distilled THF was added to the flask by a syringe. After stirring for 1 hour, a THF solution of potassium naphthalene was prepared (0.71 mmol/g). On the other hand, under nitrogen atmosphere, 50m
In a L three-necked flask, 1.96 g (5.64 mmol) of the compound represented by the formula (iA) was weighed with a syringe. The THF solution of potassium naphthalene prepared above was added thereto at room temperature for 7.85.
g was added dropwise. Aging was carried out for 1 hour, and 9.77 g (0.5%) of a polymerization initiator (IA) solution in THF was added.
8 mmol/g) was obtained. At this time, neither precipitation of salts nor cloudiness was observed ((IA) mass/THF solution mass=22.3% by weight). The substance amount ratio of the polymerization initiator (IA) synthesized by the above reaction and the starting material alcohol (iA) is 98:2 (mol %). The reaction scheme is shown below.

[Synthesis Example 5] Synthesis of compound represented by formula (I-1A) A stirrer was placed in a 500 mL four-necked flask connected with a thermometer, a dropping funnel and a Dimroth condenser. After maintaining the degree of vacuum in the apparatus at 10 Pa or less, the inside of the apparatus was heated by using an oil bath and a heat gun to remove water in the system. Then, under a nitrogen stream, 1.69 g of a THF solution of the compound represented by the formula (IA) prepared from [Synthesis Example 4-1] and 140 g of distilled THF were added into a 2 L four-necked flask. 20 g of ethylene oxide and 40 g of distilled THF were put into the dropping funnel, and the mixture was gradually dropped into a 500 mL four-necked flask. After confirming that the temperature in the 500 mL four-necked flask was stable, aging was carried out at 45 to 50° C. for 8 hours. The reaction scheme is shown below.

After completion of the reaction, the oil bath was removed and the reaction system was cooled to room temperature. A small amount of the obtained reaction solution was sampled, the reaction was stopped with acetic acid, and GPC measurement was performed. As a result, Mw=8,000, Mw/
It was Mn=1.04.

[Synthesis Example 6] Synthesis of Compound Represented by Formula (IIA) [Synthesis Example 6-1] Synthesis of Compound Represented by Formula (IIA) In a reaction solution of the compound represented by Formula (I-1A). , 2-bromoethyl methyl ether 2
． 41 g and 10.5 mL of a THF solution (1 mol/L) of potassium tert-butoxide were added, and the mixture was stirred under reflux for 5 hours. After removing the salt in the reaction solution by filtration, 25
Concentrated to wt% and transferred the concentrate to a dropping funnel. 201 g of hexane was put into a 500 mL beaker containing a stirrer, and the concentrated liquid was added dropwise thereto over 10 minutes, followed by aging for 20 minutes. After filtering the generated white powder, the powder was returned to the original beaker, washed with 99 g of hexane for 20 minutes, and the same washing operation was performed once. The reaction scheme is shown below.

The obtained white powder was vacuum dried, and as a result, 18.6 g of polymer (IIA) was obtained. GP
As a result of C measurement, Mw=8,000 and Mw/Mn=1.05.

[Synthesis Example 6-2] Alternative synthesis of compound represented by formula (IIA) 2.05 g of 2-methoxyethyl p-toluenesulfonate was added to a reaction solution of the compound represented by formula (I-1A). 0.50 g of potassium tert-butoxide was added, and the mixture was stirred at 40° C. for 5 minutes.
Stir for hours. After removing salts in the reaction solution by filtration, the reaction solution was concentrated to 25 wt% and the concentrated solution was transferred to a dropping funnel. Add 200 g of hexane in a 500 mL beaker containing a stir bar,
The concentrated liquid was added dropwise thereto over 10 minutes, followed by aging for 10 minutes. After filtering the generated white powder, the powder was returned to the original beaker, washed with 100 g of hexane for 10 minutes, and the same washing operation was performed once. The reaction scheme is shown below.

The obtained white powder was vacuum dried, and as a result, 18.6 g of polymer (IIA) was obtained. GP
As a result of C measurement, Mw=8,000 and Mw/Mn=1.05.

[Synthesis Example 6-3] Alternative synthesis of compound represented by Formula (IIA) A 2 L high-pressure gas reaction vessel was dried by nitrogen purging, and the above-mentioned [Synthesis Example 4-under nitrogen atmosphere].
1.] A THF solution of the polymerization initiator (IA) synthesized by the method 1] 8.29 g (1.02 mmol/
g, 8.46 mmol) and 885 g of distilled THF were added. After the temperature of the reaction vessel was raised to 45° C., 100 g of ethylene oxide was continuously injected, and the pressure in the system was reduced to 0 by nitrogen pressure.
． The pressure was adjusted to 15 MPa. When stirred at 45° C., the pressure in the system gradually decreased, and after 6 hours, the pressure became stable at 0.11 MPa, which was the end point of the reaction. After cooling to 40° C., 9.75 g of 2-methoxyethyl-p-toluenesulfonate as an electrophile was added to THF 97.
Dissolve in 5 g, press fit into the system, and further add potassium tert-butoxide in THF (1 m
21 ml of ol/L) was diluted with 21 g of THF and the mixture was press-fitted into the system. Then, aging was performed for 5 hours while maintaining the temperature at 40°C. The deposited salt is separated by filtration, and the adsorbent KW-2000 is added to the filtrate in an amount of 1
After adding 7 g and stirring for 2 hours, the adsorbent was removed by filtration. Concentrate the reaction solution to 400 g
After that, 750 g of hexane and 750 g of ethyl acetate were placed in a 3 L beaker containing a stir bar, and the resulting reaction solution was added dropwise, followed by aging for 10 minutes. After filtering the produced white powder, the powder was returned to the original beaker, washed with 375 g of hexane and 375 g of ethyl acetate for 10 minutes, and the same washing was repeated again, and then the obtained white powder was vacuum dried. result,
96 g of polymer (IIA) was obtained. As a result of GPC measurement, Mw=1,400, M
It was w/Mn=1.03. The reaction scheme is shown below.

As shown in Table 1 below, it is understood that in Synthesis Example 6-3, the polymerization with ethylene oxide proceeds stoichiometrically.

[Synthesis Example 7] Synthesis of Compound Represented by Formula (IIIA-a) [Synthesis Example 7-1] Synthesis of Compound Represented by Formula (IIIA-a) [Synthesis Example 6-1] in a 50 mL three-necked flask. 1.0 g of the compound represented by the formula (IIA) obtained in 1., THF 9.0 g, 1N HClaq. 0.4 ml was added and the mixture was stirred at 40° C. for 4 hours. After that, the reaction was stopped with 0.2 ml of a 25 wt% NaOH aqueous solution. After concentrating the reaction solution and distilling off water, 5.7 g of THF was added to adjust the concentration of the polymer solution, and the precipitated salt was filtered. Hexane (10 g) was placed in a 100 mL beaker containing a stirrer, and the resulting reaction solution was added dropwise, followed by aging for 10 minutes. After filtering the generated white powder, the powder was returned to the original beaker, washed with 5 g of hexane for 10 minutes, and the same washing operation was performed once.

As a result of vacuum drying the obtained white powder, 0.7 g of a compound represented by the formula (IIIA-a) was obtained. As a result of GPC measurement, Mw=7,900 and Mw/Mn=1.05. The reaction scheme is shown below.

The compound represented by the formula (IIA) may be deprotected by adding hydrochloric acid without purification after the reaction, in which case the process can be further simplified.

[Synthesis Example 7-2] Alternative synthesis of compound represented by Formula (IIIA-a) In a 1 L three-necked flask, 100 g of polymer (IIA) obtained in [Synthesis Example 6-3] and MeO.
400 g of H and 5.00 g of acetic acid were added and the mixture was stirred at 35° C. for 3 hours. Thereafter, the reaction was stopped with 24.12 g of 28% sodium methylate methanol solution. The reaction solution was concentrated and the solvent was replaced with toluene to prepare 450 g of a polymer solution, and the precipitated salt was filtered. 100 g of the adsorbent KW-2000 was added to the obtained polymer solution and treated at 35° C. for 1 hour to remove a trace amount of salt. 1000 g of hexane and 500 g of ethyl acetate were placed in a 3 L beaker containing a stirrer, and the resulting reaction solution was added dropwise, followed by aging for 10 minutes. After filtering the generated white powder, the powder was returned to the original beaker, washed with 600 g of hexane and 300 g of ethyl acetate for 10 minutes, and the same washing operation was performed once.

As a result of vacuum drying the obtained white powder, 90 g of a polymer (IIIA-a) was obtained. G
As a result of the PC measurement, Mw=11,000 and Mw/Mn=1.03. The reaction scheme is shown below.

[Synthesis Example 8] Synthesis of compound represented by Formula (IIIB-a) The same as in Synthesis Examples 4 to 7 except that the compound represented by Formula (iA) is changed to the compound represented by Formula (iB). A compound represented by the formula (IIIB-a) was obtained by the operation of. That is, the formula (i
The compound represented by B) is used to synthesize a polymerization initiator (IB) by the same operation as in Synthesis Example 4-1 and the polymerization initiator is used to perform the same operation as in Synthesis Examples 5 to 7. (IIIB-a)
A compound represented by The same operations as in Synthesis Example 6-1 for Synthesis Example 6 and Synthesis Example 7-1 for Synthesis Example 7 were performed. Regarding the compound represented by the formula (IIIB-a), G
As a result of the PC measurement, Mw=7,900 and Mw/Mn=1.05. The reaction scheme is shown below.

[Synthesis example 9] Synthesis of compounds represented by formulas (IIIA-b) to (IIIA-f) Almost the same as in synthesis examples 4 to 7 except that the ratio of the compound represented by formula (iA) and ethylene oxide is changed. Polymers (IIIA-b) to (IIIA-f) were synthesized by performing operations. The same operations as in Synthesis Example 4-1 for Synthesis Example 4, Synthesis Example 6-1 for Synthesis Example 6, and Synthesis Example 7-1 for Synthesis Example 7 were performed. The analysis results are shown in Table 2.

[Synthesis Example 10] Synthesis of compounds represented by the formulas (IIIB-b) to (IIIB-f) A substantially same operation as in Synthesis Example 8 except that the ratio of the compound represented by the formula (iB) and ethylene oxide is changed. By carrying out, Polymers (IIIB-b) to (IIIB-f) were synthesized.
The analysis results are shown in Table 3.

[Synthesis Example 11] Formulas (IIIA-g) to (IIIA-1), (IIIB-g) to (IIIB)
-L) Synthesis 2-bromoethyl methyl ether as a substrate in [Synthesis Example 6-1] is represented by the following table. 2-Bromoethyl (substituted) alkyl having an alkyl group (R ⁴ ) (having a substituent) at the end By performing substantially the same operation as in Synthesis Examples 4 to 7 except for changing to ether, the compound of formula (IIIA-g
The compounds represented by formulas (IIIB-g) to (IIIB-1) were synthesized by performing substantially the same operations as in Synthesis Example 8 on the compounds represented by formulas (III) to (IIIA-1). The same operations as in Synthesis Example 4-1 for Synthesis Example 4, Synthesis Example 6-1 for Synthesis Example 6, and Synthesis Example 7-1 for Synthesis Example 7 were performed. The analysis results are shown in Tables 4 and 5.

[Synthesis Example 12] Purification of compound represented by formula (IIIA-a) The inside of a cartridge filled with 50 g of cation exchange resin DIAION PK-208 (manufactured by Mitsubishi Chemical Corporation) was washed with 300 g of 1N hydrochloric acid and then ion-exchanged. The cartridge was washed 3 times with 300 g of water and then once with 300 g of methanol. A 5 wt% solution of polymer (IIIA-a) in methanol (polymer content: 10 g) was charged into a 500 mL two-necked flask, and the polymer solution was transferred into the above-mentioned cartridge using a pump. The methanol solution coming out from the drainage port of the cartridge was put in the original 500 mL eggplant flask, and this operation was continued for 2 hours to adsorb the polymer (IIIA-a) on the cation exchange resin. Then, the resin in the cartridge was washed once with 300 g of methanol, and then 7N ammonia solution (methanol solution,
The polymer (IIIA-a-2) was eluted from the cation exchange resin using 50 g of Kanto Chemical Co., Inc. The purified polymer after the elution step from the cation exchange resin (IIIA
-A-2).

Even if the compound represented by the formula (IIA) is used in place of the compound represented by the formula (IIIA-a), deprotection proceeds with a methanol solution under a cation exchange resin catalyst. Purification could be done simultaneously, further simplifying the process.

The obtained eluent was transferred to a 500 mL eggplant-shaped flask, and ammonia and methanol were distilled off using a rotary evaporator. After concentration under reduced pressure until the mixture was almost dried, the solvent was replaced with toluene to prepare a polymer (IIIA-a-2) having a solid content concentration of 25 wt %.

100 g of hexane and 50 g of ethyl acetate were mixed in a 500 mL beaker containing a stir bar, and a 25 wt% solution of the polymer (IIIA-a-2) obtained using a dropping funnel was added dropwise over 10 minutes, followed by stirring for 20 minutes. And then aged. After filtering the generated white powder, the powder was returned to the original beaker, washed with a mixed solvent of 50 g of hexane and 25 g of ethyl acetate for 20 minutes, and the same washing operation was performed once.

As a result of vacuum-drying the obtained white powder, 8.51 g of a polymer (IIIA-a-2) was obtained. As a result of GPC measurement, Mw=8,000 and Mw/Mn=1.05. Incidentally, when the reaction was carried out in the same manner as in the above example except that the reaction was intentionally mixed with a small amount of water at the time of polymerization, a compound obtained by concentrating and drying the filtrate obtained by the above cation exchange resin purification In this, a very small amount of by-product H-N represented by the following formula (VIIIa) due to water mixed in during the polymerization was used.
It was confirmed by MR. From the above, even if water is mixed during the polymerization, the by-product can be removed by the cation exchange resin, and the production margin can be widened.

[Comparative Synthesis Example 1] Synthesis of polymer (VIa) In a 500 mL four-necked eggplant flask connected with a thermometer, a dropping funnel, and a Dimroth condenser, potassium methoxide (manufactured by Kanto Chemical Co., Inc.) was used as a stirrer and a polymerization initiator. ) 71 mg (1.01
mmol) was added and the degree of vacuum in the apparatus was maintained at 10 Pa or less, and then the apparatus was heated using an oil bath and a heat gun to remove water in the system.

Then, 40 μL of methanol (manufactured by Tokyo Kasei Kogyo Co., Ltd.) in a four-necked flask under a nitrogen stream.
(1.00 mmol) and 140 g of distilled THF were added, and the mixture was stirred at room temperature until potassium methoxide was completely dissolved. The substance amount ratio of the polymerization initiator potassium methoxide synthesized by the above method and the starting material alcohol, methanol, is 50:50 (mol %).

A mixed solution of 35 g of ethylene oxide and 60 g of distilled THF was put into the dropping funnel, and the mixture was added little by little into the four-neck flask while keeping the internal temperature at 35°C or lower. After dropping the whole amount, set the internal temperature to 50°C.
Stirring was carried out for 80 hours while maintaining the following.

After confirming that there was no change in the conversion of ethylene oxide, acetic acid 0.0
6 g was added. After removing ethylene oxide by nitrogen bubbling, 500 mL of reaction liquid
The mixture was transferred to an eggplant-shaped flask, and the reaction solution was concentrated using a rotary evaporator until a solid was precipitated. 23 g of the crude polymer product was redissolved in 46 g of toluene and transferred to a dropping funnel.

138 g of isopropyl ether was put into a 500 mL beaker containing a stirrer, and the polymer solution was dropped using a dropping funnel over 10 minutes, followed by aging for 20 minutes. After filtering the generated white powder, the powder was returned to the original beaker, and 2 g of the mixed solvent of 69 g of isopropyl ether was added.
Washing was performed for 0 minutes, and the same washing operation was performed twice. The reaction scheme is shown below.

The white powder obtained was vacuum dried, and as a result, 18.54 g of a comparative polymer (VIa) was obtained. As a result of GPC measurement, Mw=7,200 and Mw/Mn=1.16.

[Comparative Synthesis Example 2] Synthesis of polymer (IXa) Polymer (VIa) 10.00 g, THF 29.5 g, 10 in a 300 ml four-necked flask.
0.5% by weight aqueous solution of potassium hydroxide, 0.5 g of H ₂ O, 1.06 of acrylonitrile
g, and the mixture was stirred at room temperature for 6 hours. After the reaction, alkali adsorbent "Tomita AD700
NS" (trade name, synthetic aluminum silicate, manufactured by Tomita Pharmaceutical Co., Ltd.) was added, and 2.
The reaction was carried out over time. After filtering the alkaline adsorbent, the filtrate was transferred to a 300 mL round-bottomed flask, and the solvent was replaced with toluene to concentrate the comparative polymer (IXa) until the solid content concentration became 25 wt %.

100 g of hexane and 50 g of ethyl acetate were mixed in a 500 mL beaker containing a stirrer, and the concentrated liquid obtained using a dropping funnel was added dropwise over 10 minutes, followed by aging for 20 minutes. After filtering the generated white powder, the powder is returned to the original beaker, and 50 g of hexane and 25 g of ethyl acetate are added.
The mixed solvent of was washed for 20 minutes, and the same washing operation was performed once. The reaction scheme is shown below.

The white powder obtained was vacuum dried, and as a result, 9.12 g of a comparative polymer (IXa) was obtained.
As a result of GPC measurement, Mw=7,300 and Mw/Mn=1.15.

[Comparative Synthesis Example 3] Synthesis of polymer (IIIc) 5.0 g of polymer (IXa), 5.0 in a 500 mL autoclave for hydrogen reduction.
g of Raney cobalt catalyst R-400 (manufactured by Nikko Rica Co., Ltd.), 45.0 g of methanol, 3
． 0 mL of a 1N methanol solution of ammonia (manufactured by Aldrich) was added at room temperature. After that, hydrogen gas (pressure=10 kg/cm ² ) was enclosed, and the inner temperature was heated to 120° C.,
The reaction was carried out for 6 hours as it was. After cooling to room temperature, the pressure was returned to atmospheric pressure, and then ammonia in the system was removed while blowing nitrogen. After removing the Raney cobalt catalyst by filtration, the filtrate was transferred to a 100 mL round-bottomed flask, and ammonia and methanol were distilled off using a rotary evaporator. After concentration under reduced pressure to dryness, 4.5 g of a mixture of the polymer (IIIc) and the following general formulas (IVc) to (VIc) was obtained. As a result of GPC measurement, Mw=7,
It was 300 and Mw/Mn=1.25. The reaction scheme and by-products are shown below.

[Analysis of Impurity Content of Products Obtained in Synthesis Examples 7-1, 8 and 12 and Comparative Synthesis Example 3]
Impurity contents in the products obtained in [Synthesis Example 7-1], [Synthesis Example 8] and [Synthesis Example 12] and the products obtained in [Comparative Synthesis Example 3] were analyzed. The results are shown in Table 6 below.
The compound represented by mPEG in Table 6 is a compound corresponding to the general formula (VIc) in [Comparative Synthesis Example 3], and is a compound obtained by β-elimination of acrylonitrile from a polymer having a cyanoethyl group at the terminal. The composition ratio of mPEG was calculated by H-NMR measurement. First, [Synthesis Example 7-
1], [Synthesis Example 8], [Synthesis Example 12] and [Comparative Synthesis Example 3], each containing 10 mg of the product.
Weigh it out, dissolve it in 0.75 ml of CDCl3, and add 50 ml of trifluoroacetic anhydride.
g, and left for 1 day. A proton derived from the ester α-position methylene of the compound represented by the following general formula (VI-1) and a proton derived from the amide α-position methylene of the compound represented by the following general formula (III-1) are formed by this treatment. The composition ratio of mPEG was calculated from the ratio.
In the [Comparative Polymer Synthesis Example 3], the compounds represented by the secondary and tertiary amines in the table are represented by the general formula (IVc).
, (Vc). The amount of contamination was measured by GPC and calculated from the area percentage of the polymer corresponding to the 2-fold and 3-fold molecular weight.
From these results, in the comparative polymer (IIIc), β-elimination of acrylonitrile by hydrogen reduction and formation of secondary and tertiary amines were observed, but the polymers of the examples (IIIA-a) and (I
IIB-a) and (IIIA-a-2), their by-products were not observed.

[Metal analysis of products obtained in Synthesis Examples 7-1, 8 and 12 and Comparative Synthesis Example 3]
A high frequency inductively coupled plasma mass spectrometer (ICP-MS) of the products obtained in [Synthesis Example 7-1], [Synthesis Example 8] and [Synthesis Example 12] and the product obtained in [Comparative Synthesis Example 3]. , Ag
Ilent Technologies 7500 cs) for metal impurities analysis. For the measurement, a sample obtained by diluting each product with ultrapure water 100 times was used and analyzed by the standard addition method. The analysis results (solid content conversion value) are shown in Table 7 (unit is ppb).
As a result of metal analysis, in the comparative polymer (IIIc), the heavy metal used in the reduction is mixed, whereas in [Synthesis Example 7-1], [Synthesis Example 8], and [Synthesis Example 12], no heavy metal catalyst is used. Therefore, it is understood that the example polymers (IIIA-a), (IIIB-a), and (IIIA-a-2) do not contain heavy metals.

[Synthesis of Polymerization Initiator and Comparative Polymerization Initiator and Solubility Comparison in Polymerization Solvent]
The results of synthesizing polymerization initiators (initiators 2-9, 11, 12 and comparative initiators 1-8) other than those used above are shown below. In addition, in the following, "initiator 1" is a polymerization initiator represented by the formula (IA) synthesized by using the compound represented by the formula (iA) in [Synthesis Example 4-1]. "Agent 10" is a polymerization initiator (IB) synthesized using the compound represented by Formula (iB) in [Synthesis Example 8].

[Synthesis of Initiator 2]
Initiator 2 was synthesized in the same manner as in [Synthesis Example 2-3] and [Synthesis Example 4-1] except that ethylene glycol used in [Synthesis Example 2-3] was changed to diethylene glycol. ..

[Synthesis of Initiator 3]
The method described in [Synthesis Example 2-4] and [Synthesis Example 4-1], except that the electrophile (iiB) used in [Synthesis Example 2-4] is changed to the following electrophile (iiC). Initiator 3 was synthesized in the same manner.

[Synthesis of Initiator 4]
Initiator 4 was synthesized in the same manner as in [Synthesis of Initiator 3] except that the ethylene glycol used in [Synthesis Example 2-4] was changed to diethylene glycol.

[Synthesis of Initiator 5]
[Synthesis Example 2-4] and [Synthesis Example 2-4] except that the electrophile (iiB) used in [Synthesis Example 2-4] was changed to the following electrophile (iiD) and ethylene glycol was changed to triethylene glycol.
Initiator 5 was synthesized in the same manner as in the method described in Synthesis Example 4-1].

[Synthesis of Initiator 6]
With the method described in [Synthesis Example 2-4] and [Synthesis Example 4-1], except that the electrophile (iiB) used in [Synthesis Example 2-4] is changed to the following electrophile (iiE). Initiator 6 was synthesized in the same manner.

上記求電子剤（ｉｉＥ）及び開始剤６中、ＴＢＳはｔｅｒｔ−ブチルジメチルシリルの
ことである。

In the electrophile (iiE) and the initiator 6, TBS is tert-butyldimethylsilyl.

[Synthesis of Initiator 7]
With the method described in [Synthesis Example 2-4] and [Synthesis Example 4-1], except that the electrophile (iiB) used in [Synthesis Example 2-4] is changed to the following electrophile (iiF). Initiator 7 was synthesized in the same manner.

[Synthesis of Initiator 8]
With the method described in [Synthesis Example 2-4] and [Synthesis Example 4-1], except that the electrophile (iiB) used in [Synthesis Example 2-4] is changed to the following electrophile (iiG). Initiator 8 was synthesized in the same manner.

[Synthesis of Initiator 9]
With the method described in [Synthesis Example 2-4] and [Synthesis Example 4-1], except that the electrophile (iiB) used in [Synthesis Example 2-4] is changed to the following electrophile (iiH). Initiator 9 was synthesized in the same manner.

[Synthesis of Initiator 11]
15.7 g of 6-amino-1-hexanol and 91.0 THF in a 300 ml three-necked flask.
g and 46.3 g of potassium carbonate were charged, and then 28.4 ml of allyl bromide was added dropwise while cooling with ice under a nitrogen atmosphere. Then, the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered and distilled under reduced pressure to obtain 13.2 g (yield 50.0%) of the raw material alcohol (iC) of the initiator 11. continue
Initiator 11 was synthesized in the same manner as in [Synthesis Example 4-1].

[Synthesis of Initiator 12]
Initiator 12 was synthesized in the same manner as [Synthesis of Initiator 11] except that allyl bromide was changed to 1,2-bis(chlorodimethylsilyl)ethane.

[Synthesis of Comparative Initiator 1]
Silyl-protected amino group-containing alcohol compound (iiA-2) used in [Synthesis example 2-1]
Then, Comparative Initiator 1 was synthesized in the same manner as the method described in [Synthesis Example 4-1].

[Synthesis of Comparative Initiator 2]
Comparative initiator 2 was synthesized in the same manner as described in [Synthesis of comparative initiator 1] except that trimethylsilyl (TMS) was used instead of triethylsilyl as a protecting group.

上記比較開始剤２中のＴＭＳはトリメチルシリルのことである。

TMS in the above comparison initiator 2 is trimethylsilyl.

[Synthesis of Comparative Initiator 3]
The 6-amino-1-hexanol used in [Synthesis of Initiator 11] was replaced with 3-amino-
Comparative initiator 3 was synthesized in the same manner as in [Synthesis of Initiator 11] except that 1-propanol was used.

[Synthesis of Comparative Initiator 4]
Comparative initiator 4 was synthesized in the same manner as in [Synthesis example 4-1] except that the following raw material alcohol (iD) was used instead of the compound represented by formula (iA).

[Synthesis of Comparative Initiator 5]
Comparative initiator 5 was synthesized in the same manner as in [Synthesis Example 4-1] except that the following raw material alcohol (iE) was used instead of the compound represented by Formula (iA).

[Synthesis of Comparative Initiator 6]
The 6-amino-1-hexanol used in [Synthesis of Initiator 12] was replaced with 3-amino-
Comparative initiator 6 was synthesized in the same manner as in [Synthesis of Initiator 12] except that 1-propanol was used.

[Synthesis of Comparative Initiator 7]
Comparative initiator 7 was synthesized in the same manner as described in [Synthesis of comparative initiator 3] except that benzyl bromide was used instead of allyl bromide used in [Synthesis of comparative initiator 3].

[Synthesis of Comparative Initiator 8]
A compound represented by the following formula (iF) was synthesized by the reaction shown in Scheme 1 below. Other than using the compound represented by the formula (iF) instead of the compound represented by the formula (iA),
Comparative initiator 8 was synthesized in the same manner as the method described in [Synthesis example 4-1].

1) Synthesis of Boc protection (iF-1) In a 200 ml three-necked flask, 5.11 g of 3-amino-1-propanol, 7.21 g of triethylamine, 55.43 g of methanol, di-tert-butyl dicarbonate (hereinafter Boc2O).
15.61 g was charged, and the mixture was stirred under a nitrogen atmosphere at room temperature for 14 hours. The reaction solution was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The obtained ethyl acetate solution was concentrated under reduced pressure to obtain 10.73 g (crude yield 90%) of Boc-protected (iF-1).

2) Synthesis of TBS protection (iF-2) Boc protection (iF-1) 10.61 g, THF 241.80 in a 500 ml three necked flask.
g, and with ice cooling under a nitrogen atmosphere, 9.26 g of imidazole and 15.3 TBSCl.
8 g was added. After returning to room temperature and stirring for 22 hours, the reaction was stopped with a saturated ammonium chloride aqueous solution, and the mixture was extracted with isopropyl ether. The obtained isopropyl ether solution was concentrated under reduced pressure to obtain 18.24 g (crude yield 93%) of TBS-protected (iF-2).

3) Synthesis of Boc protection (iF-3) In a 500 ml two-necked flask, 10.01 g of TBS protection (iF-2), dehydrated THF155.
58 g was added, and n-butyllithium/hexane solution (2.
69M) 16.68 mL was added dropwise. After stirring at the same temperature for 30 minutes, the Boc2O/THF solution (
26 wt%) 40.87 g was dropped, and the mixture was returned to room temperature and stirred for 2.5 hours. The reaction solution was diluted with isopropyl ether, washed with a saturated aqueous solution of ammonium chloride, and the obtained solution was concentrated under reduced pressure to give 14.77 g of TBS-protected (iF-3) (crude yield 100%).

4) Synthesis of alcohol (iF) TBS-protected (iF-3) 14.77 g, THF 110.59 in a 500 ml three-necked flask.
Then, 39.5 mL of TBAF (tetra-n-butylammonium fluoride)/THF solution (1M) was added while stirring at room temperature under a nitrogen atmosphere. After stirring at the same temperature for 5 hours, the mixture was diluted with isopropyl ether and washed with ultrapure water. The obtained isopropyl ether solution was concentrated under reduced pressure to obtain 10.22 g of alcohol (iF) (crude yield 98%).

上記スキーム中Ｂｏｃはｔｅｒｔ−ブトキシカルボニルのことである。

Boc in the above scheme is tert-butoxycarbonyl.

The structures of the various polymerization initiators synthesized above (initiators 1 to 12 and comparative initiators 1 to 8) are summarized below.

Next, the results of the solubility of the initiators 1-12 and the comparative initiators 1-8 in the polymerization solvent are shown. The initiators 1 to 12 and the comparative initiators 1 to 8 synthesized above were distilled off under reduced pressure, the polymerization initiators were taken out, and then dissolved in a polymerization solvent at a concentration of 20 wt%. "○" was shown when no turbidity was visually observed, "X" was observed when turbidity was observed or did not dissolve at all, or decomposed at the stage of making the alkoxide, and "-" was noted when not examined. ..

When the synthesis of the comparative initiators 1, 2, 5, 6 was examined, the exchange of protective groups in the molecule proceeded, but in the initiators 1, 2, 6, 7, 10, 12 with the extended chain length, The initiator is stable and
And it was dissolved in the solvent. On the other hand, the compounds which were not dissolved in the solvent with the comparative initiators 3, 4, 7, 8 were also dissolved in the solvent with the initiators 3, 4, 5, 8, 9, 11 whose chain length was extended.

As a result of the above Examples and Comparative Examples, in Synthetic Example 5 and Comparative Synthetic Example 1, the latter requires a polymerization time of 80 hours due to the presence of the starting material alcohol, whereas the former requires the starting material alcohol. It can be seen that the polymerization reaction is completed within 8 hours by using the polymerization initiator that is soluble in THF even when the remaining amount of is small. That is, the method of the present invention realized the polymerization of alkylene oxide under mild conditions. Further, in Synthesis Example 6, the process can be greatly simplified by directly using the reaction solution of Synthesis Example 5 in the reaction of the next step without post-treatment. Furthermore, in Synthesis Example 12, by using an organic solvent for the purification of the resin using the ion exchange resin, it became possible to purify the polymer by a simple method without using freeze-drying in the final step.

In Synthetic Examples 5 to 8 and Comparative Synthetic Examples 1 to 3, the latter requires a hydrogenation reaction using a heavy metal as a catalyst for the reduction of the cyano group, whereas the former requires deprotection of the protected amino group to give the desired polymer. Can be synthesized. In the comparative polymer (IIIc), β-elimination of acrylonitrile and formation of secondary and tertiary amines occur due to hydrogen reduction, but the polymer of the example (IIIA-a),
In (IIIB-a) and (IIIA-a-2), neither generation was observed (Table 6).
.. Further, in Synthesis Examples 7-1, 8 and 12 and Comparative Synthesis Example 3, as a result of metal analysis, the heavy metal used in the reduction was mixed in the comparative polymer, whereas in Synthesis Examples 7-1, 8 and 12, the heavy metal catalyst was used. It can be seen that no heavy metal is mixed in because no is used. Moreover, the amount of potassium metal mixed could be reduced by purification with a strongly acidic cation exchange resin (Table 7).
As a result, according to the present invention, the synthesis of the amino group-containing narrowly dispersed polyalkylene glycol derivative free from the inclusion of heavy metals, which may have an adverse effect on pharmaceuticals, was achieved. In addition, by synthesizing a novel protected amino group-containing alcohol and using it as a raw material as a polymerization initiator, it became possible to apply it to various polymer syntheses. Using the novel polymerization initiator,
Further, if necessary, by purification with a cation exchange resin, it is possible to remove the diol polymer, which was difficult to separate due to the mixing of water, and to obtain the amino group-containing narrowly dispersed polyalkylene glycol derivative with high purity. It has become possible and the manufacturing margin has been expanded.

The polymer compound produced using the method of the present invention can be widely used as a starting material when synthesizing a block copolymer used in applications such as pharmaceuticals and cosmetics including the field of drug delivery systems. .. In addition, the novel metal salt of protected amino group-containing alcohol can be applied to various polymer synthesis.

Claims (3)

A silyl-protected amino group-containing alcohol compound represented by the following general formula (6).

(In the general formula (6), each R ¹ is independently a straight-chain C 1-6 linear or branched or cyclic C 3-6 monovalent hydrocarbon group, or R ¹ is It is also possible to combine with each other to form a 3- to 6-membered ring with the silicon atom to which they are bonded, R ² is a group in which one hydrogen atom has been removed from the n-butyl group, and R ⁵ is a group having 2 carbon atoms. Is an alkylene group of 8 and m represents an integer of 1 to 3). A method for producing a silyl-protected amino group-containing alcohol compound represented by the general formula (6) according to claim 1, comprising a step of subjecting a trisilyl protected compound represented by the following general formula (8) to a base treatment. A method for producing a silyl-protected amino group-containing alcohol compound.

(In the general formula (8), R ¹ , R ² , R ⁵ , and m are as defined for the general formula (6), and R ¹ , R ² , R ^{5 in the} general formula (6) are represented. , And m) A silyl-protected amino group-containing polyalkylene glycol compound derivative represented by the following general formula (II-1).

(In the general formula (II-1), R ^1's each independently represent a straight chain having 1 to 6 carbon atoms, or a branched or cyclic monovalent hydrocarbon group having 3 to 6 carbon atoms, or R 1 ¹ can also be bonded to each other to form a 3- to 6-membered ring with a silicon atom to which they are bonded, R ² is a group in which one hydrogen atom is eliminated from the terminal carbon of the n-butyl group, R ⁴ is a hydrogen atom or an optionally substituted linear, branched or cyclic hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group may contain a hetero atom, R ⁵ is an alkylene group having 2 to 8 carbon atoms, m is an integer of 1 to 3, and n is an integer of 1 to 450).